Archive for January, 2009

Geron’s Oligodendroglial Precursor Cell Therapy Trial

January 27, 2009

Geron’s Oligodendroglial Precursor Cell Therapy Trial
by Wise Young, PhD MD.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082
Posted 26 January 2009, updated 29 January 2009

On January 21, 2009, Geron announced that they received the approval of the U.S. Food and Drug Administration (FDA) to do the first clinical trial that will evaluate the safety of cells derived from human embryonic stem cells (HESC). The trial will transplant oligodendroglial precursor cells (OPC’s) derived from an early HESC line isolated in 1997 by Jamie Thomson and colleagues in Wisconsin.

This is a landmark trial not only because it is the first trial of an HESC-derived cell but because it is the first such trial for spinal cord injury. HESC’s are derived from blastocysts, the first stage of development after fertilization. Geron had funded the work of Jamie Thomson in the late 1990’s.  President George W. Bush banned federal funding of research on HESC derived after August 2001.

In 1999, John McDonald and his colleagues [1] transplanted predifferentiated mouse embryonic stem cell into contused spinal cords of rats, comparing them against fibroblasts expressing neurotrophins. At 2-5 weeks, the transplanted cells had differentiated into astrocytes, oligodendroglia, and neurons, migrating as far as 8 mm from the injury site. Gait analysis showed that the transplanted rats showed better hindlimb weight support and partial hindlimb coordination.

In 2005, Faulkner & Keirstead derived [2] oligodendroglial progenitor cells (OPC) from human embryonic stem cells.  OPC’s transplanted into rat spinal cord at 7 days after contusion enhanced remyelination and improved locomotor recovery [3].   In other studies, Keirstead, et al. showed that contused rat spinal cords undergo progressive demyelination [5], OPC implants were not harmful in rats [6], transplanted OPC cells replaced oligodendroglia [7], and myelin loss is greater in contusion injury [8] and older animals [9].

Armed with this data, Geron proposed to carry out a phase 1 clinical trial to evaluate the safety of transplanting OPC derived from human embryonic stem cells (HESC) on people with subacute spinal cord injury. This would be the first time any cell from a known and well-characterized human embryonic stem cell line would be used to treat any condition. It was also the first proposal to use HESC-derived cells to treat human spinal cord.

Geron did extensive studies of the safety and mechanisms of OPC effects on spinal cord injury. In 2006, Zhang, et al. [10] reported that the HESC-derived OPC secrete neurotrophic factors, suggesting an alternative mechanism for the beneficial effects of the cells on recovery after contusion injury. In 2007, Okamura, et al. [11] reported that the HESC-derived OPC cells do not stimulate strong immune responses in vitro, providing the rationale for using non-HLA matched heterologous cells.

From 2005 on, Geron repeatedly announced their intentions to transplant the HESC-derived OPC cells into people with spinal cord injury but the FDA did not approve the clinical trial [12]. It became clear that FDA approval of the first HESC-derived cell transplant faced significant scientific [13] and bioethical hurdles [14]. In May 2008, the FDA placed a hold on the Geron’s application [15] but Geron said that they were addressing the concerns and were confident of approval [16].

On January 21, 2009, Geron announced that the FDA approved the application for the [17]. The media response was massive [18]. The story was carried by almost every news source [18-20]. The community response was initially strongly positive. Coming on the 3rd day after President Barack Obama’s inauguration, some thought that the approval of the first HESC trial was due to Obama’s coming to power.

The exuberance faded as people read the fine print. First, the trial is not for people with chronic spinal cord injury. It is intended to be used within 2 weeks after injury for people with complete thoracic spinal cord injury. Second, the goal of the trial is to show safety and feasibility, not necessarily efficacy. Third, the cells have been differentiated to the point that they are no longer acting as stem cells but only as oligodendroglia.

The trial focuses on subacute spinal cord injury in part because animal data suggest that the cells alone would be effective only when transplanted into rats within two weeks after injury. This does not necessarily mean that the cells would not be effective in chronic human spinal cord injury, especially when combined with some other therapy (such as chondroitinase, Cethrin, or Nogo-A antibody).

The trial is designed to establish safety of the cells. One worry of the FDA and the scientific community is that HESC will produce teratomas (a stem cell tumor).  Geron played it very safe. They differentiated these cells so that they produce only oligodendroglial cells and are very unlikely to produce teratomas. They chose to transplant the cells into patients with thoracic complete spinal cord injuries so that if the cells turned into tumors, the neurological consequences will be minimized.

According to the New York Times by Andrew Pollack [21], Thomas B. Okarma, Geron’s chief executive, did not think that the Bush Administration’s objections to embryonic stem cells delayed approval. “We really have no evidence, ” Dr. Okarma said, “that there was any political overhang.” But Robert Klein, chairman of California Institute of Regenerative Medicine thought that Bush had pressured the FDA.

Some scientists were critical of the trial. For example, according to the Pollack article, John A. Kessler, who is chair of Neurology and director of the Stem Cell Institute at Northwestern University and father of a spinal-injured daughter, said that a treatment might not apply to more seriously injured people. “We really want the best trial to be done for this first trial, and this might not be it,” he said.

Kessler was referring to the use of myelinating cells to treat people with so-called “complete” spinal cord injury. People with such severe injuries should have fewer axons crossing the injury site to myelinate.  Okarma responded that this trial was designed to establish the safety of the treatment and lack of efficacy in this trial was not a problem.

The same article cited Steven Goldman, chair of neurology at the University of Rochester, “It’s not ready for prime time, at least in my mind, until we can be assured that the transplanted cells have completely lost the capacity for tumorogenicity.” Okarma pointed out that Geron has done numerous studies to show that the cells do not contain any residual embryonic stem cells and did not form tumors when transplanted into animals, even after a year.

Geron’s application for the clinical trial was over 22,000 pages long and the preparatory work cost $45 million. While Okarma said that he did not think that the Bush Administration impeded the application for this particular trial, he did think that the Federal government slowed the progress in the field by making it difficult for researchers to do embryonic stem cell research. Clearly, given the $45 million and 4 years required for the approval of the clinical trial, it was not an easy process.

Geron’s web site and news reports indicate that the trial will treat 8-10 patients who are within 2 weeks after “complete” thoracic spinal cord injury. It will probably start in July 2009. However, many details are unclear. Before the FDA placed a hold on the trial application in May 2008, Geron had said that the cells would be transplanted into the spinal cord of patients undergoing spinal cord decompressive surgery and all the patients will receive a 2-month period of pharmacological immunosuppression . It is not clear that the same regimen will be used.

In the meantime, the reaction of the spinal cord injury community has ranged from exuberance over the approval of the first HESC trial [22] to deep pessimism over comments by Okarma, who said that people with “complete” spinal cord injury have no chance of recovering any function, or something to this effect. Many people in the spinal cord injury community [23] were disappointed at being excluded from the study which is only for the newly injured.

As John Smith commented in CareCure [25]:

Tom Okarma is cool, groovy, dope or whatever other adjective you might use to convey a leader with media savvy. Our 21st century world is so ravenous to scoop one another there is little respect for the truth and process.

I’ve met the man. I’ve spoken to him privately twice and questioned him about Geron’s commitment to SCI and the meaning of this trial for chronics. This trial is of staggering importance for Geron and those of us living the life. However, it is not momentous for us in the sense of being a cure-all.

There is no way Okarma is going to speculate beyond the scope of this trial’s goals. That would be a terrible error in judgment and one to which he is immune. He is a doctor and a scientist, not a snake oil salesman. He is also the CEO of Geron. Their reputation is on the line with this trial. I admire him for the self-control necessary to put a brake on the message.

I asked him point blank, one on one, away from the glare of cameras and the notepads of journalists what this trial meant for chronics. He repeated what was quoted in the various articles reporting on the FDA approval. Evidence exists that this therapy will not work for chronics due to scarring.

My son is six years post injury. Naturally, his answer was disappointing. But, of course, that is not the end of the story, though it is likely that is all Okarma will dare to say on the subject.

He knows all about efforts to deal with the scar tissue that range from bridging the injury site to dissolving the scar to the work headed by Keirstead at UCI (post #13). Nonetheless, he’s not going to comment on that or leapfrog the purpose of the current trial. He is going to stay on point. Bless him for that; now is not the time to get sidetracked from the journey ahead.

As this trial proceeds through its various stages, the world of SCI research is going to be turned upside down. In part, it will be due to the incredible science funded by Geron. It will also be because of the confluence of research supported by the soon to be minted CDRPA, Stem Cell Research Enhancement Act, The CIRM and ongoing studies conducted by the likes of Dr. Davies, Dr. Keirstead, Dr. Kerr, the China-SCI Network and others.

I’m 62, and I plan on seeing my son walk again. I accept that curing SCI is a process. So, hold on, it’s going to be quite a ride.

Others thought that the Geron trial is opening doors for other companies and other trials. ChipS [26] pointed out:

I think all the pessimists are missing the big picture here. First off, this is a huge hurdle that has been overcome. The political tide is changing, and to have this trial announced on the heals of this transition will establish a new era of support for this type of work.

Next, this study involves only the limited lines of hESC that was developed prior to the 2001 ban. Given the promised policy change that will likely overturn that ban on fed funding for new lines, this could increase the possibilities of the effectiveness for more treatments in the very near future.

Now that this news has been plastered all over the internet and TV news, the public has been reminded that there are many people suffering from paralysis who are hoping for this trial to be a success. Publicity is an ally. We need to do our part to exploit this opportunity. Write letters to congress, local papers, ect…

Lastly, now that Geron has been given the green light and popped the FDA’s cherry on these types of trials, many more start-ups will be able to come to join the party. Suddenly, all is possible again. Geron took a huge gamble here. The fate of the company is riding on this. I am praying this is a success. This had to happen here. I suspect that other nations will soon follow suit as many labs will be collaborating internationally and sharing information in an attempt of cracking the next walnut, and gaining a foothold in this new and promising market.

Good things are coming folks. It may not be as soon as we want, but the flood gates are cracked and are opening more and more.

In summary, the first clinical trial of cells derived from human embryonic stem cells has been approved by the U.S. FDA and will soon start. It is not the trial that many hoped to see, i.e. a trial that will show that human embryonic stem cells cure spinal cord injury. Rather, it is a small trial to assess the safety and efficacy of transplanting oligodendroglial precursor cells derived from one of the first human embryonic stem cell lines isolated in 1997. The trial will test the cells in patients that are within 2 weeks after severe spinal cord injury. Its most likely outcome is to show that these cells can be safely transplanted to the spinal cord. If this trial is successful, it will lead to other trials. This is the first and an important step.

References

1. McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, Gottlieb DI and Choi DW (1999). Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med 5: 1410-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10581084

2. Faulkner J and Keirstead HS (2005). Human embryonic stem cell-derived oligodendrocyte progenitors for the treatment of spinal cord injury. Transpl Immunol 15: 131-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16412957

3. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K and Steward O (2005). Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci 25: 4694-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15888645

4. Nistor GI, Totoiu MO, Haque N, Carpenter MK and Keirstead HS (2005). Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49: 385-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15538751

5. Totoiu MO and Keirstead HS (2005). Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 486: 373-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15846782

6. Cloutier F, Siegenthaler MM, Nistor G and Keirstead HS (2006). Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm. Regen Med 1: 469-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17465839

7. Yang H, Lu P, McKay HM, Bernot T, Keirstead H, Steward O, Gage FH, Edgerton VR and Tuszynski MH (2006). Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. J Neurosci 26: 2157-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16495442

8. Siegenthaler MM, Tu MK and Keirstead HS (2007). The extent of myelin pathology differs following contusion and transection spinal cord injury. J Neurotrauma 24: 1631-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17970626

9. Siegenthaler MM, Ammon DL and Keirstead HS (2008). Myelin pathogenesis and functional deficits following SCI are age-associated. Exp Neurol 213: 363-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18644369

10. Zhang YW, Denham J and Thies RS (2006). Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors. Stem Cells Dev 15: 943-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17253955

11. Okamura RM, Lebkowski J, Au M, Priest CA, Denham J and Majumdar AS (2007). Immunological properties of human embryonic stem cell-derived oligodendrocyte progenitor cells. J Neuroimmunol 192: 134-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17996308

12. Keim B (2007). The Company Who Cried Clinical Trial: Geron’s Unfulfilled Stem Cell Promises. blog.wired.com. http://blog.wired.com/wiredscience/2007/07/the-company-who.html

13. Puceat M and Ballis A (2007). Embryonic stem cells: from bench to bedside. Clin Pharmacol Ther 82: 337-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17637781

14. Hviid Nielsen T (2008). What happened to the stem cells? J Med Ethics 34: 852-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19043108

15. Anonymous (2008). FDA’s delay of Geron ESC trial raises concerns. {May 15, 2008. http://www.fiercebiotech.com/story/fda-s-delay-of-geron-esc-trial-raises-concerns/2008-05-15?utm_medium=rss&utm_source=rss&cmp-id=OTC-RSS-FB0

16. Smith A (2008). Human stem cell tests could be near. CNNMoney.com. http://money.cnn.com/2008/02/11/news/companies/geron/index.htm?postversion=2008021212

17. Anonymous (2009). Geron Receives FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. Geron. http://www.geron.com/media/pressview.aspx?id=863

18. Anonymous (2009). Geron Corp. (GERN) Gains FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. http://blogs.finditt.com/QualityStocks/Post.aspx?postID=32925

19. Coghlan A (2009). Historic trial to treat spinal injury with stem cells New Scientist http://www.newscientist.com/article/dn16475-historic-trial-to-treat-spinal-injury-with-stem-cells.html

20. Madrigal A (2009). FDA OKs First Human Trials of Embryonic Stem Cells Wired. January 23, 2009. http://blog.wired.com/wiredscience/2009/01/fda-approves-em.html

21. Pollack A (2009). F.D.A. Approves a Stem Cell Trial. New York Times. January 23, 2009. http://www.nytimes.com/2009/01/23/business/23stem.html?_r=1

22. Childs D and Bhatt J (2009). New Prez, New Studies: New Era for Stem Cells. {Jan. 26, 2009. http://abcnews.go.com/Health/President44/story?id=6727016&page=1

23. Carecure (2009). Geron. http://sci.rutgers.edu/. 27 January 2009. http://sci.rutgers.edu/forum/showthread.php?t=113884

24. Smith J (2009). Geron. Care Cure Community. 27 January 2009. http://sci.rutgers.edu/forum/showpost.php?p=990125&postcount=20

25. ChipS (2009). Geron. Care Cure Community. 27 December 2009. http://sci.rutgers.edu/forum/showpost.php?p=990160&postcount=21

An open letter to former President George W. Bush

January 25, 2009

An open letter to  former President George W. Bush

25 January 2009

Dear Mr. President,

I write to thank you sincerely for your service to the United States.  I believe that you had the best interest of the country in your heart.  Now that you have left the office, I urge you to help with the healing of the nation.

The United States is in the deepest economic recession since the Great Depression, due to the collapse of its mortgage and credit industries.  Millions of people have lost their jobs.   The crisis arose because of policies to deregulate mortgages and not to regulate subprime mortgages as collateral for our credit industry.   Your support would be helpful for Congress and President Obama to develop bipartisan legislation to regulate mortgages and credit industry.

We are fighting two wars (Afghanistan and Iraq) with no reserves to handle a third conflict.  Our enemies know that our troops are tied up in Afghanistan and Iraq.   Perhaps this is why Russia so boldly invaded Georgia and bullied Ukraine, why Iran has continued to develop nuclear weapons despite UN sanctions, and why maritime piracy is erupting around the world.     Your support of withdrawing U.S. troops from Iraq would help our armed forces rebuild and carry out other critical missions.

The U.S. government policies of rendition, detention, and torture have violated the Geneva Convention and weakened our moral position on human rights.   Torture is neither necessary nor sufficient to protect us against terrorism.  By engaging in torture, we have placed ourselves at the same moral level as terrorists and we are encouraging torture of our soldiers and civilians.   Please support the banning of torture by our government.

Finally, your decisions to restrict stem cell research, to veto Congressional legislation twice to allow stem cell research, and to suppress governmental scientists who opposed your environmental and other policies have earned you the reputation of being an anti-science president.  You have encouraged public mistrust of science by politicizing it.  I hope that you will speak up to restore trust in science again.

Thank you.

Sincerely,
Wise Young.

Is There a Conspiracy to Stop the Cure?

January 24, 2009

Is There a Conspiracy to Stop the Cure?
by Wise Young PhD MD, W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Road, Piscataway, NJ 08854-8082
posted 24 January 2009, last updated 25 January 2009

I was recently asked the following question on carecure:

Originally Posted by JWJR1970
Hello again Dr. I was wanting to ask you another question…it’s something that I’ve heard through the grapevine over the years since I’ve been injured. Hopefully you can debunk it. I’ve always heard that it’s taken this long for a cure and that “they” meaning all the pharmacuetical companies, medical equipment companies etc really don’t want a cure because there’s more money to be made if there’s not a cure. Is there any truth at all to that? Gosh I surely hope not. Well thanks again for your time! Take care! Jack

I had answered this question as follows:

The conspiracy theory that pharmaceutical companies are making so much money from spinal cord injury that they are obstructing or hiding the cure is wrong for the following reasons:
1. A cure for spinal cord injury would make them far more money than selling bandages, generic drugs such as baclofen.
2. Spinal cord injury doesn’t make any company all that much money. All the treatments for spinal cord injury are used in many conditions.
3. Many companies would love to have a cure for spinal cord injury. The problem is that they are not convinced that a cure is possible or worth the billion dollar investment they would have to make.

After thinking about the answer some more, I thought that I would expand the answer to try to put the question away once and for all. In the mid-1990’s, the internet web sites were rife with rumors that pharmaceutical companies were conspiring together to prevent the cure. In fact, some people claim that the cure had already been discovered but the companies were hiding them so that it would not take away profits that they are making from people with spinal cord injury. Like all such conspiracy theories, this comes from several false assumptions based on half-truths.

It is true that people with spinal cord injury use a lot of supplies and drugs, which some companies are profiting from. The average person with spinal cord injury probably spends $22,000 per year on drugs, supplies (catheters and other items), and durable equipment (wheelchairs, FES, and other equipment). Multiplied by 250,000, the estimated number of people that are severely disabled by spinal cord injury, this gives $5.5 billion. While not insubstantial, this market is spread out over many companies, none of whom make so much from spinal cord injury that they might be motivated to stop a curative therapy from occurring.

It is true that few companies are investing in developing curative therapies for spinal cord injury. However, companies are refraining from such investments not because they are afraid that such therapies would steal profit from their other products but because they do not believe that they can make a profit from such products.  Many companies believe that the spinal cord injury market is too small, that curative therapies for spinal cord will take too long and will cost too much to develop. If the potential market is 250,000 people, a 10% penetration into that market with $10,000 profit per person would add to only $250 million. This is not enough to warrant the average $1 billion cost of moving a therapy from discovery to market.

It is true that some wheelchair corporations will lose some business if many people with spinal cord injury no longer required wheelchairs. However, spinal cord injured people represent only a fraction of the wheelchair users, which includes people with multiple sclerosis, spina bifida, cerebral palsy, muscular dystrophy, stroke, amyotrophic lateral sclerosis, back pain, and many other problems. There is an estimated 1.6 million full-time wheelchair users in the United States [1], of which probably less than 15% have spinal cord injury.  So, the sudden loss of even all spinal cord injuries from the wheelchair market would be significant but not devastating for the industry.

It is true that some companies are having trouble getting spinal cord injury therapies into clinical trial.   For example, Geron [2] recently announced that they have received FDA approval for a phase 1 trial of oligodendroglial cell transplant to treat subacute spinal cord injury.  According to news reports, the company has spent four years and $45 million to get this therapy into clinical trial.   However, this is because it is the first human embryonic stem cell trial and it has been subject to extra scrutiny and criticism with consequent bureacratic and other delays.

It is true that Congress did not pass the Christopher and Dana Reeve Paralysis Act (CDRPA) to fund research to reverse paralysis.  The bill was obstructed for over four years in Congress despite the support of several prominent Republican legislators (such as Arlen Spector and Orin Hatch) who strongly supported both the stem cell and spinal cord injury research.  However, the CDRPA was blocked and prevented from coming to a vote.  Was there a conspiracy in Congress to stop spinal cord injury cure research? I don’t think so.  I think that it was just plain old politics.

In short, I do not believe that there is a conspiracy to stop the cure for spinal cord injury. We were simply unlucky in the last 8 years. The attack on 9/11/01 diverted the America’s resources and attention. Then we were hit by the worst finanical crisis since World War II.   We were victims of stem cell politics, first by George W. Bush when he decided to restrict federal funding of stem cell rsearch, then by a Republican Congress who refused to allow the bill to come to a vote, and then two vetoes by George W. Bush. Even the Christopher and Dana Reeve Paralysis Act became a political football that could not be passed until after Bush stepped down from office.

As Christopher Reeve once pointed out, he wouldn’t mind so much if scientists had told him that the cure was a scientifically intractable problem and that it would take many years to come up with a cure. What upset him was that scientists told him that it was doable but the problems were lack money and politics. Those were the last two obstacles he expected to slow down the cure for spinal cord injury. Money and politics are things that we can do something about. Unfortunately, we have just lost 8 years and we must move quickly to make up for the lost time.

References

1. http://www.jan.wvu.edu/media/Wheelchair.html
2. http://www.geron.com/

FAQ #4: What Can I Do Now to Be Ready for the Cure?

January 13, 2009

FAQ #4.  What Can I Do Now to Be Ready for the Cure?
By Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082
Posted 11 January 2009, last updated 13 January 2009

The fourth most frequently asked question, usually asked after the questions if a cure is possible, when it will be available, and whether it would be applicable to chronic spinal cord injury, is what people can do to prepare for the cure.  Obviously, the first priority should be to take care of the body, to prevent muscle and bone atrophy, and other changes that prevent recovery of function.

Muscles undergo atrophy when they are not used.  Such atrophy is reversible.  Spasticity naturally prevents atrophy and therefore should not be over suppressed with drugs.  Standing will prevent atrophy of extensor anti-gravity muscles and will exercise balancing reflexes.  Stimulating muscles for certain functions, such as walking and standing, can rebuild muscles.

Bones also undergo atrophy when not used.  Until recently, no therapy had been shown to be effective for reversing bone loss after spinal cord injury. Recent studies suggest that the bisphosphonate alendronate restores bone mineral density but it is not clear that it increases bone strength and reduces fracture risk.   So, it seems reasonable to do both, i.e. weight bearing and alendronate.

It is also common sense to avoid irreversible surgery.  For example, tendon transfers, the Mitrofanoff procedure and bladder augmentation, colostomy, and sphincterotomy can significantly improve quality of life but may not be readily reversible.  People should recognize that the surgery may not be reversible.

What about locomotor training? Many studies suggest that weight-supported treadmill training can restore unassisted ambulation, even after severe incomplete spinal cord injury.  However, recent studies suggest that toverground walking may achieve similar results in people with incomplete spinal cord injuries.

Finally, what should we do about the brain?  Over half of the brain is devoted to input from and output to the spinal cord.  Non-use of neurons may cause atrophy or new connections in brain and spinal cord.  These connections are responsible for recovery, spasticity, spasms, and neuropathic pain.  Exercise, training, electrical stimulation, and pharmacological therapies can affect neural reorganization and function.

In the following sections, I will discuss some practical approaches to reversing atrophy of muscle and bone, some surgical therapies to avoid, the effects of locomotor training and spinal cord stimulation, the role of CNS reorganization, and the importance of education.  The goal is to provide a framework for how people can best prepare their bodies and central nervous system for recovery after spinal cord injury.

Reversing Muscle Atrophy

Immobilization causes muscle atrophy.  An immobilized leg will show measurable loss of muscle and bone calcium.  Spinal cord injury causes  muscle and bone losses in body parts innervated by spinal cord below the injury.  Muscle atrophy was recognized in the earliest descriptions of spinal cord injury [1].  Atrophy is most marked in patients with flaccid paraplegia resulting from lower thoracic or lumbar spinal cord injury [2].  Studies in rats revealed significant changes in muscles at 3, 7 and 30 days after spinal cord injury, similar to changes seen after denervation [3].  Scelsi, et al. [4] biopsied muscle from 22 paraplegic patients and found similar muscle degeneration.

Spasticity [5, 6] naturally prevents muscle atrophy.  In fact, I wonder if spasticity had not evolved as a mechanism to prevent atrophy.  In 1988, Robinson, et al. [7] showed that patients with greater spasticity had greater stimulated muscle responses and strength in their legs. While extensor spasms may interfere with transfers and flexor spasms at night may interfere with sleep [8], these activities are a form of free exercise and spasticity should not be completely suppressed with drugs.  High doses of anti-spasticity drugs, such baclofen given orally [9] or intrathecally, will reduce spasticity [10] and convert it to flaccidity [11].

Standing prevents atrophy of leg muscles. Standing is a reflex and balancing involves multiple reflexes [12].  When a person stands, pressure on the soles of the feet activates extensor muscles.  Of many approaches to rebuilding muscles [13], standing is the least costly and has extensively documented health benefits, including relief of skin pressure [14], reduction of constipation [15], improved bladder function, and better ability to straighten legs [16, 17]. Consumer pressure [18] for standing devices have led to availability of several standing wheelchairs [19] and many other standing devices.  People should utilize such devices to stand several hours every day if possible.

Functional electrical stimulation (FES) can reverse muscle atrophy.  Many devices are available, including those designed to build muscles for standing and walking [20-27], new walking orthoses [28, 29] and neuroprostheses [30-32], and treadmills for gait training [33].   FES of innervated will reverse atrophy [34].  Lower extremity functional electrical stimulation (FES) for pedaling a bicycle against variable resistance not only increases muscle endurance, speed, and strength but also increases aerobic metabolism and endurance [35, 36].  Upper limb FES can restore upper limb muscles[37, 38].  FES can also be used to assist gait [39] and will suppress spasticity as well to reduce the amount of anti-spasticity drugs [40].

High intensity stimulation is required to reverse atrophy of denervated muscles [41].  Surface FES stimulates nerves that enter and they activate the deeper musculature.  In denervated muscle, FES cannot stimulate nerves to activate deeper muscles and hence are ineffective.  Very high currents are required to penetrate into and activate deeper muscles.  However, care must be taken to use large electrode so that the currents are spread out over a large area of skin [42-47].  Such stimulation can restore even denervated muscles.

Reversing Osteoporosis

Bone loss occurs after spinal cord injury [48].  The most significant bone losses occur in the lower extremities [49, 50].  Biering-Sorenson, et al. [51] studied 6 men and 2 women with “complete” SCI for up to 53 months, comparing upper and lower extremity bone, finding that certain areas showed rapid loss but other, including the spine and femoral shaft continued to decline slowly as long as 4 years after injury.  Frotzler, et al. [52] used quantitative CT to measure bone loss and found that bone loss reached a plateau in 15 months.  The bone loss did not seem to be due to testicular hormonal levels [53].

Mechanical loading and FES-induced muscle activity reduces but does not prevent bone loss. Dudley-Javorski, et al. [54] reported their experience with one patient who performed nearly 8,000 electrically stimulated soleus muscle contractions per month in one leg, resulting in significant increases in soleus muscle torque and fatigue index of the stimulated side compared to the unstimulated control side.  Bone mass density (BMD) of the untrained leg declined by 14% during the first year but fell only 7% in the trained leg.  Shields, et al. [55] had earlier shown that FES significantly improved BMD in one leg compared to the other untrained leg.  Others [56] found no effect of FES on BMD.

The bisphosphonate alendronate [57] prevents bone loss in patients with acute spinal cord injury [58].  In 31 age- and gender-matched patients randomized to the drug or placebo, treated patients had an average of 5.3% whole body BMD and 17.6% difference in hip BMD, confirming an earlier Brazilian study [59] reporting that the drug increased bone calcium.  Sniger & Garshick [60] had reported that alendronate increases bone density in people with chronic spinal cord injury.  As early as 1999, Lyles [61] and Harris, et al. [62] were already recommending alendronate for vertebral compression fractures in older women.  Alendronate prevents the hypercalciuria after spinal cord injury [63].

Bone loss increases risk of lower extremity fractures [64] and hip instability is common in patients after spinal cord injury [65].  Increasing BMD alone may not increase strength and may make bone more brittle. Dionyssoiotis, et al. [66] studied tibial strength in 50 patients with acute and chronic spinal cord injury, comparing those that had T4-7 levels and those with T8-12 levels.  Bone strength declined significantly over time in the lower thoracic and not the upper thoracic injuries.  The authors suggested that neurogenic factors may be involved in bone loss.  Maimoun, et al. [67, 68] had concluded that neurological factors were more important than mechanical or hormonal factors.

In summary, bone loss is a serious unsolved problem in spinal cord injury.  Mechanical loading and FES-induced muscle activity will reduce but does not completely prevent bone loss in acute spinal cord injury.  The bisphophonate alendronate prevents bone loss in acute spinal cord injury and may even restore bone mineral density in chronic spinal cord injury but may not normalize bone strength.  However, a combination of mechanical loading, FES-induced muscle activity, and alendronate may be necessary to restore bone mineral density and bone strength in people with spinal cord injury.

Reversible Surgery

Surgical therapies are frequently done to improve function and to increase independence in people with spinal cord injury. These include tendon transfers for the hand, the Mitrofanoff procedure and bladder augmentation to facilitate bladder care, colostomy and sphincterotomy to reduce the time required for take care of the bowel and bladder. I will discuss some of these procedures from the viewpoint of their reversibility.   If the procedure will provide significant function, independence, or better quality of life now, people should make the decision in favor of what they need today and not wait for tomorrow.  However, they need to understand if the surgery is not easily reversible.

Tendon surgery.  Tendon transfers take part of a tendon from a muscle and transfer the power of that muscle to another that is weak.  It is useful for restoring tenodesis or ability to use fingers to oppose the thumb to pick things up and to feed oneself.  It can be used to restore the triceps, which locks the elbow and allows a person independence to transfer on their own.  Although tendon transfers are reversible in theory, I know of few occasions in which reversals were done.

Mitrofanoff procedure.  Originally developed for children with spina bifida and other conditions that compromise bladder function, this procedure uses the appendix as a conduit to the bladder through the umbilicus, allowing people to catheterize themselves through their belly button. For quadriplegic women, it is a boon because it allows them to catheterize themselves without having to take their clothes off and lying down.  The surgeon may sew a piece of intestine to the bladder wall, so that the bladder can no longer contract, allowing people to reduce anti-cholinergic drugs for bladder spasticity.  The procedure itself should be reversible since it does not interfere with the bladder sphincter at all.

Colostomy.  A colostomy is a procedure where the colon is connected to an opening in the abdominal wall, allowing feces to come out into a bag.  It is a blessing for many people who spend hours every morning doing their bowel routines and for people with fecal incontinence.  Depending on how the procedure is carried out, it can be either temporary or permanent.  Many people have had temporary colostomies that have been reversed.

Sphincterotomy.  Many men with paralyzed bladder opt for a sphincterotomy, i.e. cutting the bladder sphincter so that the urine drains through a condom catheter to a bag.  The surgery is simple and it saves work required for intermittent catheterization.  However, the sphincterotomies are probably difficult to reverse and seldom done in practice.

Of these procedures, the colostomy and Mitrofanoff should be reversible if the surgeon takes care to minimize tissue removal.  Tendon surgeries should also be reversible.  Sphincterotomies may be less reversible although they should be reparable in theory.  If the surgeon knows that there is wish for reversal of procedure, they can take precautions to preserve tissues that may be required for reversal of the procedure.  This is something that should be discussed with the surgeon.

Locomotor Training

Scientists have long known that it was possible to train animals with transected spinal cords to walk [69-71], that noradrenergic and serotonergic agonists facilitate walking [72, 73], and the mammalian lumbar spinal cord is capable of great plasticity [74] and even learning [75, 76], providing a rational basis for locomotor training in people with spinal cord injury [73].  Training cats with transected spinal cords for 30 minutes per day and 5 days a week improves their stepping ability [75, 77].  Muir & Steeves [78] showed that phasic cutaneous input facilitates locomotor recovery after incomplete spinal cord injuries in chick.  De Leon, et al. [79] showed that the animals maintained walking functions after training ended.  Kim, et al. [79] found that serotonin agonists enhanced locomotor recovery in rats that received neural transplants [80]. Although treadmill training did not affect locomotor recovery in rats after spinal contusion injury [81] and enriched environment alone facilitated walking recovery[82], many scientists speculated that treadmill training would improve locomotor function after spinal cord injury.

Treadmill training improves walking in humans after spinal cord injury.  Wernig & Muller [83] first reported in 1992 that treadmill training restored walking in people with chronic spinal cord injury. By 1995, Wernig, et al. [84] had trained 89 people, 44 of whom had chronic incomplete spinal cord injury.  The 44 subjects with chronic spinal cord injury trained for 3-20 weeks at 0.5 to 18 years after injury and 33 were unable to walk or stand unassisted before training.  By the end of training, 25 of the 33 (75%) initially wheelchair bound subjects could walk independently, 7 improved but still needed help, and one did not improve.  Only 6 of the 44 people could do staircase walking before the therapy but 34 were able to do so after training.  In 1998, Wernig, et al. [85] reported that 31 of 35 subjects maintained their locomotor improvement, 3 showed further improvement, and one lost function.

Dietz, et al. [75] similarly found in 1995 that treadmill training with body weight support modulated electromyographic activity in leg muscles, similar to healthy subjects, except that activity in the gastrocnemius (the main antigravity muscle during gait) was significantly lower.  Dobkin, et al. [86] studied the effects of weight-supported locomotor training on complete and incomplete subjects with spinal cord injury[86] and showed the sensory input associated with rhythmic locomotion can enhance the output of lumbosacral neural circuits and contribute to stepping activity.  Behrman & Harkema [87] showed that treadmill training improved ability of people to perform stepping and the training either achieved or improved overground walking.

Based on the above studies, the U.S. National Institutes of Health commissioned a multicenter study to assess treadmill locomotor training.  Dobkins, et al. [88] compared weight-supported treadmill and over-ground walking training after acute incomplete spinal cord injury.  In 146 subjects recruited at 6 regional centers within 8 weeks after injury, all had FIM-locomotor scores of <4 and were randomized to treadmill or overground training. At 6 months, both groups showed substantial improvement:  35% of ASIA B, 92% of ASIA C, and all of ASIA D subjects walked independently. There was no difference between the two treatments.

Spinal Cord Stimulation

Many scientists speculated that humans have a central pattern generator (CPG) for locomotion in the human spinal cord [89-91] and proposed the use of spinal cord stimulation to activate locomotion [92].  Hadi, et al. [93] showed that destruction of interneurons neurons in the L2  spinal cord produced lasting loss of walking ability in rats, suggesting that this is where the mammalian CPG may be located.  Ribotta, et al. [80] showed that transplantation of loecus coreulus cells to provide serotonergic innervation of L1-L2 spinal cord segment restored well-defined locomotor patterns in rats.  The serotonin agonist 8-OH-DPAT induces locomotor movements in low thoracic transected mice [94].  Yakovenko, et al [95] showed that intraspinal stimulation of spinal cords of transected rats significantly increased locomotor scores.

Dimitrijevic, et al. [96, 97] reported evidence of a spinal central pattern generator and showed that stimulation of this center improved gait in people after spinal cord injury.  The center can be readily stimulated with epidural electrodes placed over the L2 spinal cord [98, 99].  The stimulation initiates extension of lower limb [100] and can produce stepping-like movements [101] in subjects with complete spinal cord injury.  In both complete and incomplete spinal cord injury, reorganization of the spinal cord circuitry provides alternative mechanisms of locomotor and motor control [102, 103].  In 2007, Mianssian, et al. [104] found that human lumbar cord circuitry can be activated by extrinsic tonic input to generate locomotor-like activity.  Early application both FES and CPG stimulation may be helpful in preventing disuse atrophy of both muscle and neurons.

CPG stimulation helps locomotor training.  Barriere, et al. [105] pointed out the important role of the central pattern generator in the recovery of voluntary locomotion. Herman, et al. [106-108] has shown that epidural stimulation of the T10/T12 central pattern generator in humans facilitates walking recovery in people with chronic spinal cord injury, improving walking speed and endurance while reducing the sense of effort by the subject.  In particular, Carhart, et al. [107] described a patient with chronic incomplete tetraplegia in whom partial weight-bearing therapy alone was insufficient to achieve functional ambulation.  However, application of the T10/T12 stimulation not only produced further improvements in treadmill walking but facilitated transfer of these gains to overground walking.  The participant initially reported a reduction in the sense of effort for overground walking from 8/10 to 3/10 (Borg scale) and was able to double his walking speed to 0.35 m/sec and distance to 325 m.

Spinal cord stimulation facilitates walking not by directly activating neurons that control walking but by lowering the threshold to activate walking and to recruit additional muscles that may not be under voluntary control.  The stimulation not only increases the efficiency and speed of walking but reduces both perceived and actual effort required for walking, including metabolic energy utilization during walking [106].  Recent studies suggest that the electrodes don’t even have to be placed epidurally but can activate the spinal cord when placed on skin overlying the lumbar cord [104, 109]. Note that rhythmic auditory stimulation likewise has strong entrainment effects on gait cadence, velocity, and stride length in patients with incomplete spinal cord injury [110].

Plasticity

Over half of the brain is devoted to processing sensory and motor signals coming from or going to the spinal cord.  What happens to the parts of the brain that are longer receiving and no longer having a place to send commands to?  Early studies by Goldberger, et al. [111-114] had shown that local neurons sprout to fill in synaptic sites vacated by injured axons.  Depending on the source of the sprouting axons, the neuron may become suppressed or hyperexcitable.

Jain, et al. [115] found new brainstem connections in adult monkeys after dorsal column transection, where face afferents from the trigeminal would grow into the cuneate nucleus, expanding the face region into the hand region of the somatosensory cortex. Kaas, et al. [116] reported that damage to sensory afferents in the spinal dorsal columns render the corresponding parts of the primary somatosensory inactive to tactile stimulation and initiate maladaptive neuronal circuitry, including hyperalgesia [117].  If some dorsal column afferents are present, they will activate larger portions of the somatosensory cortex.

The corticospinal tract (that directly connects the cortex to spinal cord) reorganizes after spinal cord injury. Diffusion tensor imaging show progressive degeneration and sprouting of spared fibers in the corticospinal tract [118].  Corticospinal evoked potentials revealed enhanced pathways targeting muscles rostral (above) to the spinal injury [119] and stimulating remaining pathways produces exaggerated motor responses.  Hayes, et al. [120] used magnetic transcranial stimulation to reinforce reflexes in patients after spinal cord injury.

The spinal cord proximal to the injury site also reorganizes.  Functional MRI studies of rats after midthoracic spinal cord injuries show that small sensory stimuli that would not normally activate spinal cord also activate neurons in the dorsal horn of spinal cord below the injury site [121]. People show exaggerated startle responses in muscles proximal to the injury site [122].  Hand motor evoked potentials in people with chronic complete thoracic spinal have longer central conduction times [123].

The spinal cord below the injury site also changes.  Except for loss of motoneurons [124] and second lesions in the lower spinal cord [125, 126], circuits in spinal cord below the injury site often show increased recurrent inhibition after injury [127].   Konya, et al. [128] found proliferation of endogenous neural stem cells, increased immunoreactivity of serotonin and synaptophysin, and faster neurite growth/sprouting after anastomoses of functional nerves with distal nerves.  Peripheral nerve injury induces more reorganization of spinal circuits below the injury site [129].

The brain and spinal cord above and below the injury site are plastic and reorganize after injury, often in response to a variety of inputs.  Exercise and other activities in the brain and spinal cord are likely to affect both brain and spinal cord after injury, including spasticity and neuropathic pain. Much of the recovery of locomotor and other functions occur solely because of this reorganization and not regeneration [130].

Education

Many studies indicate that one of the best predictor of quality of life after spinal cord injury is education level.  According to Smith, et al. [131], higher levels of education were associated with lower odds of FMD (frequent mental distress), FDS (frequent depressive symptoms), and poor or fair health in U.S. veterans with spinal cord injury. More education in the United States is associated with greater Internet use and higher quality of life [132].  In Canada, individuals with more formal education had better quality of life [133].  Likewise, education predicts quality of life quotients in Europe [134-136].  But there are other reasons for education.

Understanding of the mechanisms and treatments of spinal cord injury is essential for informed decisions concerning therapies.  In the coming years, many therapies are likely to be claimed beneficial for spinal cord injury.  Not all the therapies will be appropriate for everybody.  People must become expert on spinal cord injury and treatments.  You will not only help yourself but also become a better advocate for the cure by understanding what is needed.  There is a lot of learn and the earlier that you start, the better it will be.

Learning the normal anatomy and physiology of the spinal cord is the first step.  It would be useful for people to know the dermatomes and segmental representation of the muscle, how signals are conducted in the spinal cord, and how different sensations are represented in spinal cord tracts.  In addition to helping people evaluate their own recovery, it will allow them to understand their doctors and communicate.

Understanding the pathophysiology of spinal cord injury is the second step.  For example, it would be helpful for people to understand the mechanisms of spasticity and neuropathic pain, what causes syringomyelia, and autonomic dysreflexia.  Most people have little idea of why spinal cord injury causes all these problems.

Knowing what must be accomplished to restore function is the third step.  For example, it is important to understand regeneration.  A common misconception is that spinal nerve fibers or axons are like wires and that all one has to do is to reconnect the wires.  Axons are living parts of neurons.  When axons are injured, the part that has been separated from the cell dies.  Regeneration means regrowing axons back to their original connection.

Keeping up with the latest advances regarding therapies for spinal cord injury is important because our understanding of treatments is moving so quickly.  Stem cells are only the latest wave and it is important to know what they can and cannot do.  The cells alone are unlikely to facilitate regeneration and replace neurons.  They need to be applied in combination with growth factors, growth inhibitor blockers, and other treatments, as well as repetitive exercise to reverse learned non-use.

Education is the best guarantor of the cure.  If you don’t know the normal anatomy and physiology, don’t understand the pathophysiology and what must be done to restore function, and are not up on the latest information concerning therapies, you depend on the knowledge and understanding of others.  You don’t have to know and understand it all but the more you know, the more likely you will make the best decision.

Summary and Conclusions

What should a person do now to be ready for the cure?  First, people should prevent and reverse atrophy of muscle and bone.  Second, they should avoid surgical procedures that are irreversible.  Third, locomotor training can restore ambulation, particularly after incomplete injuries.  Fourth spinal cord stimulation may help locomotor training.  Fifth, the brain and spinal cord reorganizes after injury.  Finally education is important, not only because academic achievement improves quality of life after spinal cord injury but people also need to understand their injury and the therapies to make informed decisions.

Spasticity prevents muscle atrophy.  It is free exercise and people should avoid taking so much anti-spasticity drugs that their muscles are flaccid.  Standing exercises reflexes responsible for weight bearing and balance.  Electrical stimulation (FES) can reverse atrophy.  Normally, surface stimulation depends on muscle innervation to activate deeper muscles.  Higher intensity stimulation is required to activate deeper muscles and reverse atrophy of denervated muscles.

Osteoporosis or bone loss occurs after spinal cord injury.  Bone loss occurs primarily in parts of the body that are paralyzed.  Reinstatement of mechanical stress on bone, i.e. standing, is often not sufficient to rebuild bone.  Recent clinical trials suggest that the bisphosphonate alendronate prevents bone calcium loss but it is unclear that this drug restores bone strength.  Mechanical loading and FES-induced muscle activity probably should be combined with mechanical stress to rebuild bone.

Certain surgical procedures improve quality of life.  For example, tendon transfer can restore hand or arm function while tendon lengthening can reduce need for anti-spasticity medication.  The Mitrofanoff procedure allows people to catheterize themselves through their belly button.  Combined with augmentation, it reduces need for drugs to prevent bladder spasms.  A colostomy or sphincterotomy may reduce time and effort needed for bowel and bladder routines.  However, people should understand that these procedures are not easily reversible and they should discuss this with their surgeons.

Locomotor training can be beneficial, even in people with severe incomplete injuries who have not walked for many years after spinal cord injury.  A recent clinical trial showed that treadmill and overground training have similar benefits, restoring unassisted ambulation in over 90% of people during the first year after incomplete spinal cord injury.  Walking is programmed into the spinal cord and few spinal axons are required to initiate walking.  Spinal cord stimulation can reduce effort, speeds up, and increases efficiency of walking.

The brain and spinal cord undergoes extensive reorganization after spinal cord injury.  Spasticity, spasms, and neuropathic pain are a result of reorganization.  Exercise and training may reduce or alter spasticity and neuropathic pain.  Finally, education is important not only because formal educational achievement is one of the best predictor of quality of life after spinal cord injury but people need to learn as much as possible about their condition and the treatments that may help them.

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FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?

January 3, 2009

FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?
By Wise Young, Ph.D., M.D., Rutgers University
W. M Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082

Will a cure work for chronic spinal cord injury?  Many people are anxious that all the treatments that they hear about seem to be aimed at acute spinal cord injury.  When they look at their bodies, they ask how any therapy can restore a body that has been paralyzed and senseless for years, in some cases decades.  How will therapy restore muscle and bone?   Not surprisingly, many people with chronic spinal cord injury think that the cure is for the newly injured and not for those with chronic spinal cord injury.

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons. First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.  Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.  Third, many people recover function years after injury.  These observations give me hope that there will be therapies that will restore function in chronic spinal cord injury.

Most of my reasons for hope do not stem from animal studies of spinal cord injury but from many years of observing people with spinal cord injury.  People can and do recover after injury, often years afterwards.  I have seen people recover when their spinal cords have been decompressed or an arteriovenous malformation has been obliterated, often after years of paralysis and sensory loss.  Sometimes the recovery is rapid, suggesting that connections were present but suppressed.  Other times, the recovery occurs over weeks, suggestive of remyelination.  The recovery may take years, suggestive of regeneration.

Before discussing these reasons for hope, I want to first deal with several misapprehensions that many people seem have about their spinal cord injury.  Over the years, many people have expressed surprise when I have told them that the spinal cord below the injury site is alive and kicking.  They think that the spinal cord below the injury site is “dead”.  Another common belief is that it is not possible to restore atrophic muscle and bone that have become flaccid and osteoporotic.  Finally, there is a general notion that the spinal cord is far too complex for it to be reparable with a dash of cells, a squirt of growth factors, and a sprinkle of growth inhibitor blockers.   These concerns are understandable.

Common Misapprehensions about Spinal Cord Injury

Many people are anxious that the therapies will not work for chronic spinal cord injury. Some believe that the spinal cord below the injury site is “dead” and cannot be revived.  Other think that chronic spinal cord injury is associated with many changes of the body that cannot be reversed, including atrophy of muscle and bone.  Finally, most people are concerned that the spinal cord is too complex to be repaired by transplanting some cells, splashing on some growth factors, blocking a few axonal growth inhibitors, and exercising.  Let me address these concerns first.

Isn’t the spinal cord dead below the injury site?  Christopher Reeve asked me once why his legs move whenever his respirator filled his lungs with air.  Aren’t they supposed to be paralyzed?  I answered that Penelope is there waiting for Odysseus to come home, referring of course to the Greek myth where Penelope is Odysseus’ wife waiting for him to come home from a long journey.  Many suitors are knocking on her door.  Like the neurons in the spinal cord below the injury site, she is impatient for her husband’s return.  Spasticity and spasms are proof that the spinal cord is alive and kicking. People who have flaccid paralysis below the injury site may have had some damage to the spinal cord below the injury site.  However, this does not necessarily mean that the spinal cord is “dead”.  It does mean that there is insufficient excitability to cause spasticity and spasms.

Can we reverse nerve, muscle and bone atrophy?  It takes time and a lot of work but activity can and will reverse the bone and muscle loss.  For example, recent studies suggest that even completely denervated muscles can be restored with intense electrical stimulation.  Astronauts who stay for prolonged periods of time in microgravity lose bone just like people in spinal cord injury but bone will return as the person spends time weight bearing in normal gravity.  Finally, the central nervous system is like muscle and bone in that it also undergoes atrophy when it is not active.  Called “learned non-use”, the central nervous system “forgets” its function.  Much evidence suggests that learned “non-use” could be reversed by intensive repetitive exercise.

Isn’t the spinal cord is too complex to repair and restore?  How can we hope to restore millions of connections between the brain and spinal cord?  It turns out that the spinal cord is not only much simpler but is much capable and plastic than we had ever imagined.  Your brain doesn’t control muscles directly when you walk.  The brain simply turns on the walking program that resides in the spinal cord and then modulates it to go faster slower, to turn, to slow down, to turn, etc.  The central pattern generator (CPG) resides in the L2 spinal cord and controls walking.  One does not need many axons to initiate and control walking.  That is why both humans and animals can walk with only 10% of the nerve fibers in their spinal cord.

In summary, the spinal cord below the injury site is alive and often kicking.  Flaccidity simply means insufficient excitability.  Although it takes time and a lot of work, atrophy of nerves, muscles, and bone can be reversed.  The spinal cord can learn and possess programs for movements, including walking.  It doesn’t take a lot to turn the programs on and control them.  That is why people with 10% of their spinal cord can walk.

The Ten Percent Rule

Less than ten percent of the spinal cord is necessary and sufficient to support complex functions such as walking.  We know from animal studies that rats and cats can walk with less than 10% of the spinal tracts crossing an injury site [1].  This is true for humans as well.  In the 1980’s, I use to do evoked potential monitoring [2, 3] for Fred Epstein, a neurosurgeon who operated on spinal cord tumors of kids.  He would often cut open the spinal cord and remove the tumor, leaving behind spinal cord that is thin that it is almost transparent.  On the Upper East Side of New York, there used to be bagel store where some Chinese guy would cut lox that is so thin that you could almost see through it.  That was what the spinal cord of these kids looked like and yet they would walk out of the hospital.

How do people walk with so little spinal cord?  The brain doesn’t directly control the muscles used for walking.  The spinal cord does [4].  All the movements for walking a programmed into the spinal cord [5].  To start walking, the brain sends a message to the spinal cord to tell it to walk [6].  A center in the L2 spinal cord called the central pattern generator (CPG) initiates and coordinates the muscles responsible for walking [7, 8].  The CPG is of course why chickens can continue to run around after their heads have been cut off [9].  It is also the reason why we can sleepwalk at nights.  You don’t need much of your brain to walk.  In fact, it is possible to stimulate the lower spinal cord at L2 and activate walking and the CPG is under sensory control [10].

Herman, et al. [11-13] reported in 1999 that subthreshold stimulus (not strong enough to activate walking by itself) made it easier for people with spinal cord injury to initiate and control walking.  This is of interest for locomotor training.  Herman describes a person who is just a household walker after years of overground locomotor training, normally taking over 160 seconds to walk ten meters.  However, when the L2 stimulator was turned out, at a level that does not activate walking, the person is able to walk 10 meters in less than half the time.  The walking recruited more muscles and the gait was more efficient.  After several months of training with the stimulator, the person is now able to walk more than a km at normal speeds.  Energy studies indicate that the walking pattern is much more efficient when the stimulator has been turned on.

Humans evolved tremendous redundancy of the spinal cord because of spinal cord injury because regeneration takes too long.  At one mm a day, regeneration may take a year or more to restore function.  No animal can survive his long without being able to escape, hunt, and procreate.  Therefore, animals (and humans) have evolved redundant spinal cords.  Such redundancy provides a major survival advantage because spinal cord injury is relatively common.  For example, although there are over a million cases of cervical whiplash every year in the United States, less than 10,000 result in spinal cord injury requiring hospitalization.  By having a redundant spinal cord, humans could survive even after 90% of their spinal cord has been damaged.  This is why a football player can keep playing after having gotten a “stinger” and people with incomplete spinal cord injury, ever severe ones destroying 90% of the spinal cord, will recover walking.

Axons Keep Trying to Grow

The first thing that I was taught in neuroscience as a graduate student was that the central nervous system cannot regenerate.  But, if you look at the injured spinal cord, this is not true.  Axons in the spinal cord not only can and do grow but continue to try growing throughout adult life.  This may sound like heresy but science is really about overturning dogmas and the dogma that the spinal cord cannot regenerate has been toppled many times over the past 20 years.  The spinal cord not only can grow and does so routinely but it continues to try to grow many years after spinal cord injury.  Let me explain.

After an injury, the spinal axons that have been damaged “die-back” a short distance and then start regrowing towards the injury site.  In most cases, they stop at the edge of the injury site, although some axons apparently will invade into the injury site itself.  In the first detailed and systematic study of axon regrowth in contused spinal cords [14], we found axonal growth into the injury site of over 70% of contused rat spinal cords at 6 weeks after injury.  Most of the axons did not grow out of the injury site but they have clearly grown up to and into the spinal cord.   Many axons, however, stop at the injury and appear to be waiting.

Ramon y Cajal [15] first described these waiting axons.   They have enlarged bulbous endings that he called “sterile terminal bulbs”.  He thought that these were just axons that had been damaged and could not grow.  The problem is that you can find these at 2 week, 2 years, and even 20 years after injury.  My friend Richard Bunge [16] once showed me a slide of a human spinal cord 20 years after injury.  The spinal cord was from a woman who had died 20 years after injury.  At the injury edge, thousands of axons with their bulbous endings were present, as if they were waiting.  This amazed me. Were these axons just sitting there for 20 years?  That seemed highly unlikely.

The answer to this question did not come to me until I saw a talk once by Jerry Silver.  He was trying to get axons to grow in culture dishes.  To mimic the inhibitory growth environment of the spinal cord, he and his students had coated a cell culture with laminin (which supports axonal growth) and put a drop of solution containing chondroitin-6-sulfate-proteogylan or CSPG (which stops axonal growth).  As the drop of CSPG solution dried, it left a concentration gradient of CSPG that was lowest at the center of the drop zone and highest at the drop edge.  Jerry then placed a dorsal root ganglion in the center of the drop zone and took videos of the dorsal root ganglion axons growing.

When an axon grows, it forms a growth cone at the tip.  In its fast growth mode, the growth cone is like a spearhead.  However, as axons grow in a progressively growth inhibitory environment, the growth cones tend to spread out.  They eventually stop and become bulbous terminals.  In his useful insight way, Jerry called these “frustrated” growth cones.  When viewed in on video, one can see that axons start growing, becoming frustrated, and then falling back, repeatedly trying over and over again.  The fact that these terminal bulbs are present in spinal cord 20 years after injury tells me that there is continued regrowth in the spinal cord, probably for the entire life of the individual.  Even if it did not, there are probably ways to kickstart the growth again.

Give Them a Path and They will Take it All the Way

In the 1980’s, Sam David and Alberto Aguayo [17, 18] literally stood the non-regeneration dogma on its head when they hypothesized that spinal axons can grow but that there are growth inhibitors in the spinal cord that stops growth.  To test the hypothesis, they excised a peripheral nerve, one end into the cervical spinal cord and the other end into the lumbar spinal cord of a rat.  Spinal axons grew into the nerve inserted into the spinal cord (on both sides) and all the way to the other end.  However, they would not re-enter the spinal cord on the other side.

In 1999, I heard Thomas Carlstedt [19] of the Royal National Orthopedic Hospital at Stanmore speak about his work inserting avulsed brachial plexus nerves back into the spinal cord.  Brachial plexus injuries cause avulsion of the spinal root from the cord.  He would expose the spinal cord and insert the avulsed nerve back into the spinal cord.  Several months later, all the patients recovered some movement in their paralyzed arm.  In fact, some of these patients had “breathing arms” because their arms would move as they breathed, suggesting that the axons that normally activate breathing have entered into the peripheral nerve to the arms.  To me, this is proof that if you give spinal axons a path to grow, they will take it and go all the way.

Giorgio Brunelli, et al. [20] used peripheral nerves to bridge from the spinal cord above the injury site to muscles below the injury site.  He started by using a branch of the ulnar nerve that innervates the little finger side of the hand and moving the nerve to the sciatic nerve of the leg, to innervate the leg muscles.  He has done this to a number of people but moved from this procedure to doing a nerve bridge from above the spinal cord to muscles below the injury site [21]. Brunelli et al. [22, 23] have shown that glutamatergic spinal axons from the spinal cord innervate muscle.

Shaochen Zhang [24] has done thousands of peripheral nerve grafts above the injury site to muscles below the injury site, not only from arms to the legs but from neck to arms, from upper arm and shoulder nerves to the hand, and from intercostal nerves to the bladder and legs.  Xiao, et al. [25-30] has been diverting the L2 or L3 ventral root to reinnervate the pudendal nerve (S2), which innervates the bladder.  This procedure restores bladder function in close to 80% of patients.  Scratching the dermatome for L2 can initiate micturition (bladder voiding).  Many patients were able to produce a 3-foot stream of urine.  The procedure seems to work in spinal cord injury and spina bifida.

To me, the finding that spinal axons will grow into peripheral nerves and connect cells at the end is proof that they can regenerate and that all you have to do is give them a path and they will take it all the way.  They will make synapses with the cells that they find at the end, including muscles.  But, even more amazing was the finding somatic motor nerves from the lumbar cord will reinnervate and make the bladder function again.  This is amazing because micturition (the act of urination) is a complex act that involves bladder contraction and relaxation of the bladder sphincter and ability to stop when the bladder is empty.  For a somatic nerve to mediate this complex response is amazing.

Recovery is Possible in Chronic Spinal Cord Injury

Recovery is the rule and not the exception after spinal cord injury.  Since most people have incomplete spinal cord injury, a majority of people recover substantial function.  Even those with so-called “complete” spinal cord injuries usually recover 1 or more segments.  This may come as a surprise to most people who are used to being told that people do not recover after spinal cord injury. Spontaneous recovery from spinal cord injury provide several insights into the mechanisms [31].  First, recovery is often slow and may take years. Second, repetitive training facilitates and accelerates the recovery.  Third, absence of function does not necessarily mean that the structures are absent. These will be discussed in turn below.

Most people continue to recover some function years after the original injury.  For example, Christopher Reeve, who was certified by many doctors to have a so-called “complete” spinal cord injury and did not receive any experimental regenerative therapy, begin recovering sensory about 2 years after injury, to the point that he had light touch sensation over 75% of his body [32-35].  His anal area was so sensitive that they had to use lidocaine cream during bowel procedures.  At 6 years, his wife Dana noticed that Christopher could move his left index finger.  It turns out that he has quite good control on his left index finger.  Christopher also found that he could move his legs slightly.  The time frame and nature of this recovery is consistent with the possibility of spontaneous regeneration after spinal cord injury [36].

Repetitive training can restore function even in people who have not functioned for years after injury. When a particular function has not been used for a long period of time, atrophy is not limited to bone and muscle.  It appears also to occur in the central nervous system.  Called “learned non-use”, this remarkable phenomena can be mimicked by denervating an animal’s arm by cutting the dorsal root, and then allowing the subject to stop using the arm.  After several months, the arm become effectively paralyzed.  However, intensive and repetitive exercise can restore function, even many years after injury [37].  Constraint-induced movement therapy [38] is now used to treat multiple sclerosis [39], stroke [40], and many other conditions [41].   Locomotor training is a formed of forced-use exercise [42-45] that can and has been used to restore locomotor function in people, often many years after their spinal cord injury.

Finally, neurologists have long assumed that absence of function means loss of the structure mediating the function.  However, central nervous system function can be suppressed for years without loss of structure.  For example, treating an arteriovenous malformation (AVM) or decompressing the spinal cord can result in rapid recovery of function.  I use to monitor evoked potentials of patients undergoing surgical or radiological procedures [3, 46-48].  One of the patients was a paraplegic athlete with thoracic spinal cord AVM. Although paralyzed for nearly 7 years, he recovered rapidly after the embolization and walked out of the hospital after embolization. Such rapid functional recovery could not have been due to regeneration or remyelination.  It was due to removing a cause that had suppressed function for many years.

Summary and Conclusions

Many people are concerned that the cure for spinal cord injury will apply to newly injured people and not to people with chronic spinal cord injury.  While these concerns are legitimate, it is important to dispose several common misapprehensions. First, the spinal cord is not “dead” below the injury site.  Injury disconnects the lower spinal cord from the brain and upper spinal cord. Spasticity and spasms is proof that the lower spinal cord is alive and kicking.  Second, neural, muscle, and bone atrophy can be reversed even after years of loss.  Finally, the spinal cord contains programs for complex functions such as walking.  Those should be preserved and the goal is to reconnect enough axons to initiate and modulate these programs.

About 10% of spinal cord tracts is necessary and sufficient to support complex functions, including walking.  Humans, for example, can walk even after damage to 90% of the spinal cord because the brain does not directly control walking.  All the movements for walking, for example, are programmed in the spinal cord.  The brain sends a message to the central pattern generator (CPG) in the spinal cord, telling it to walk. The CPG is located in the L2 lumbar cord and can be stimulated to initiate or facilitate walking of people after spinal cord injury.  Humans evolved redundancy of the spinal cord because regeneration is too slow to help an animal to survive after spinal cord injury.

Axons continue to try to grow after injury.  At the injury site, they die back a short distance and grow back to the lesion edge.  In contusion injuries, some axons grow into the injury site but many stop at the lesion edge.  Ramon y Cajal described axons at the injury site with terminal bulbs.  These axons with bulbous endings were present in human spinal cords even 20 years after injury.  These terminal bulbs are “frustrated” axons that are still trying to grow at the injury site, due to growth inhibitors that collect in the extracellular matrix surrounding the injury site.

If you give axons a path to grow, they will take it and grow all the way.   David & Aguayo first showed this in the 1980’s by inserting peripheral nerves into the spinal cord and showing that many axons from the spinal cord would grow into the nerve and continue all the way to the other end.  Thomas Carlstedt used this method to treat patients with avulsed brachial plexus, showing that axons from the spinal cord not only grew in the nerve by innervated muscle.  Giorgio Brunelli likewise showed that the axons that grew into the peripheral nerves were spinal axons rather than motoneurons and that they form glutamatergic synapses.  Finally, Zhang and Xiao in China diverted nerves from various parts of the spinal cord to innervate and control organs that they normally do not.

Recovery is possible in chronic spinal cord injury.  A majority of people recover substantially after spinal cord injury, particularly those with incomplete spinal cord injuries.  Even people with so-called “complete” spinal cord injuries continue to recover some function, often years after injury. Christopher Reeve is an example.  Likewise, intensive repetitive training can reverse learned non-use, including restoration of locomotion in people who have not walked for many years after spinal cord injury.  Finally, certain conditions in the spinal cord can suppress function for years and removal of the causes can result in rapid restoration of function, within days.

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FAQ #2: When will the Cure be Available for Spinal Cord Injury?

January 1, 2009

FAQ #2: When will the Cure be Available for Spinal Cord Injury?
Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Rd, Piscataway, NJ 08854-8082
First posted 23 December 2008, final version 3 January 2009

Introduction

When will a cure for spinal cord injury be available?  This is the second most frequently asked question, usually asked right after the first most frequently asked question, “Will there be a cure for spinal cord injury?” While I don’t have a crystal ball for the future, some therapies are already beginning to restore function in people with spinal cord injury with spinal cord injury, several regenerative therapies have begun clinical trials, and the first combination therapies will soon go into clinical trial.  If we work hard, the resources are available, and we are lucky, we should expect the first restorative therapies within 5 years and perhaps the first curative combination therapies within a decade.

First generation therapies for spinal cord injury are already restoring some function to some people with spinal cord injury.  Methylprednisolone (MP) was the first therapy to show any beneficial effects when given after spinal cord injury.  MP improves motor and sensory recovery by about 20% compared to control.  A second therapy is Fampridine (4-aminopyridine), which is restoring function to some people with demyelination. The third therapy is locomotor training for people with “incomplete” spinal cord injuries.

Second generation therapies are now or will soon be in clinical trial.  These include cell transplants (olfactory ensheathing glia, Schwann cells, bone marrow stem cells, neural stem cells, oligodendroglial progenitor cells, embryonic stem cells), nogo and nogo receptor blockers, chondroitinase, growth factors, lithium, and many others. These therapies are likely to stimulate modest regeneration in the spinal cord and restore more function to more people.

Third generation therapies will be combination therapies that will bring substantially more function to most people, fulfilling the definition of what many people may call “cures” for spinal cord injury.  The optimal combination will probably differ depending on the individual.  The combination therapies should include not only therapies that regenerate spinal axons but also remyelination and neuronal replacement, including motoneurons.

What can we learn from these experiences?  I will describe below eight examples of therapies for spinal cord injury, i.e. methyprednisolone, locomotor training, fampridine, cethrin, nogo antibody, and human embryonic stem cells, bone marrow stem cells, and combination therapy with cord blood mononuclear cells and lithium.  I chose these treatments because each have undergone or are going through clinical trial.  I will describe the development of each of the therapies to date, the lessons from this experience, and the probability of the first restorative therapies and combination therapies.

Methylprednisolone (MP)

MP was the first therapy shown to be effective for acute spinal cord injury.  In the 1970’s, neurosurgeons were using high doses of the anti-inflammatory glucocorticoid drug methylprednisolone (MP) to treat arachnoiditis [1] and head injury [2].  Some clinicians wondered if MP would be effective for acute spinal cord injury [3, 4].  In 1979, ten spinal cord injury centers joined to do the first double blind randomized clinical trial of high-dose and low-dose MP for acute spinal cord injury.

The first National Acute Spinal Cord Injury Study (NASCIS 1) randomized 300 patients to 1000 mg/day or 100 mg/day of intravenous MP for 10 days starting within 24 hours after injury. The trial found no significant difference between the two doses of MP [5].  However, in 1982, animal studies showed that much higher doses (30 mg/kg) were required to inhibit lipid peroxidation [6] and that very early treatment was necessary for to reduce extracellular calcium entry into cells and to prevent post-traumatic ischemia [7].  The opiate receptor blocker naloxone was beneficial in animal models [8, 9] and a phase 2 trial [10].

The second National Acute Spinal Cord Injury Study (NASCIS 2) therefore randomized 487 patients to placebo, high-dose MP (30 mg/kg bolus followed by 5.4 mg/kg/hour over 24 hours), and naloxone (5.4 mg/kg + 3.0 mg/kg/hour over 24 hours).  Starting in 1985, the trial proposed to segregate patients by the median treatment time, which was 8 hours, assess the effects of treatment timing.  NASCIS 2 [11] showed that high-dose MP improved motor and sensory recovery compared to placebo when treatment started within 8 hours but not when started later than 8 hours [12].  Naloxone had intermediate effects between MP and placebo.  MP was not associated with significant morbidity or mortality. From 1991-1993, <50% of people with acute spinal cord injury in Colorado received MP [13] and physicians tended to give the drug to more severely injured patients.

The third National Acute Spinal Cord Injury Study (NASCIS 3) randomized 499 patients with acute spinal cord injury and treated all within 8 hours with a 30 mg/kg MP bolus, followed by 5.4 mg/kg/hour for 24 hours (MP24), MP given for 48 hours (MP48), or tirilazad mesylate (TM) 2.5 mg bolus given every 6 hours for 48 hours (TM48).  The median treatment time was 3 hours.  All three treatment groups had similar outcomes when started within 3 hours but MP48 was better than either MP24 or TM48 when given more than 3 hours after injury [14, 15].  The treatments were not associated with significant mortality or morbidity except for an increase in severe pneumonia after MP48.

The NASCIS group recommended MP24 when it could be started within 3 hours, MP48 between 3-8 hours, and no MP if it could not be started within 8 hours after injury. Several randomized trials [16-19] have confirmed beneficial effects and safety of MP use in human acute spinal cord injury and related conditions [20, 21].  However, one small randomized trial [22] and several retrospective studies [23-27] suggested MP may be ineffective. One study suggested that MP Retrospective studies are biased because clinicians tend to give MP to more severely injured patients.  Nevertheless, criticisms of NASCIS mounted [28-36].  Today, MP is an option and not a standard treatment of acute spinal cord injury in the United States.

Locomotor Training

Most doctors believe that recovery of walking is unlikely after spinal cord injury and thus few encourage their patients to walk after injury.  In 1992, Wernig & Muller [37] reported that intensive treadmill training restored unassisted walking to 8 patients, starting at 5-20 months after spinal cord injury.  By 1995, Wernig et al. [38] had studied 89 patients (44 chronic, 45 acute) with spinal cord injury.  Of 44 chronic patients trained for 3-20 weeks, 33 were initially wheelchair-bound and could not stand or walk.  After training, 25 (76%) of the 33 wheelchair-bound patients achieved unassisted walking.  Of 11 patients who were walking before training, all had better speed and endurance.  In a 1998 followup [39], at 6-72 months after training, 31 of 35 chronic patients who recovered unassisted walking maintained, three improved, and one stopped walking.  Of 41 initially acute spinal cord injuries, 15 improved and one stopped walking.

In 1998, the National Institutes of Health (NIH) commissioned a multicenter study to compare weight-supported treadmill and overground walking training in spinal cord injury.  The Spinal Cord Injury Locomotor Trial or SCILT [40] showed that <10% of patients with ASIA B, 92% of those with ASIA C, and 100% of ASIA D recovered walking at >0.8 meter/second and over 260 meters in 6 minutes.  An ASIA (American Spinal Injury Association) B classification refers to an injury that preserves only sensation below the injury site, including anal sensation.  ASIA C indicate injuries that preserve anal sensation or sphincter function and motor function below the injury site but less than half of ten key muscles have strength grades exceeding 3 of 5 (0=paralyzed, 1=slight, 2=definite, 3=anti-gravity, 4=against resistance, 5=normal).  ASIA D indicates injuries with 5 or more key muscles with strength grades of 3 or more.  SCILT indicated no difference between training with weight-supported treadmill and overground walking.

Although intensive training can restore locomotion in animals after even severe spinal cord injuries [41-45], the finding that >90% of people with incomplete spinal cord injury can recover unassisted walking even without treadmill training nonetheless took many clinicians by surprise.  Despite initial resistance, this finding is transforming rehabilitation of spinal cord injury.  Motor incomplete patients can walk.  Many investigators are now examining the effects of treadmill training patients with ASIA A (complete) or B (sensory incomplete).  Others are assessing other training approaches, in combination with functional electrical stimulation [46], serotonin receptor agonists [47], and other methods of increasing motor control [48].

In summary, early studies in the 1990’s reported that weight-supported treadmill training could restore unassisted locomotion to people with chronic spinal cord injury.  In 1998, the NIH funded SCILT to study weight-supported treadmill training of patients with incomplete spinal cord injuries.  The study surprisingly showed that >90% of motor incomplete patients recovered unassisted locomotion, whether they were trained by treadmill or overground walking, suggesting that most people who have preserved motor function after injury can recover locomotion if they worked on it.  Many investigators are examining various adjuncts to locomotor training.

Fampridine (4-AP)

Trauma, ischemia, and inflammation demyelinate the spinal cord. 4-aminopyridine (4-AP or fampridine) blocks potassium channels on demyelinated axons, improves conduction, and increases neurotransmitter release [49].  In 1981, Bostock, et al. [50] reported that 4-AP improves conduction in demyelinated axons and Zangger, et al. [51] showed that it also facilitates L-DOPA induced spinal locomotor rhythms in spinal-injured animals.  In 1986, Eliasson, et al. [52] showed that 4-AP restores conduction in heat-injured nerve and spinal roots in animals.  In 1987, Bowe, et al. [53] confirmed that 4-AP improves conduction in demyelinated axons and Blight & Gruner [54] found that 4-AP improved vestibulospinal free fall responses in spinal-injured cats.  In 1989, Blight et al. studied the effects of 4-AP in dogs [55] and proposed clinical trials of 4-AP in spinal cord injury.

In 1993, Hansebout, et al. [56] did the a double-blind, crossover trial of 4-AP in eight patients, finding the drug improved motor and sensory function.  Hayes, et al. [57] confirmed the 4-AP effects on function [58] and motor evoked potentials [59] in patients with spinal cord injury.  In 1997, Segal & Brunnemann [60] found that 4-AP improves pulmonary function in quadriplegic humans with chronic spinal cord injury [60].  In 1997, Acorda Therapeutics licensed the use patent for 4-AP treatment of spinal cord injury. In 1998, Potter, et al. [61] did a randomized crossover trial of a sustained release 4-AP (Fampridine SR) made by Elan.  In 1999, Acorda partnered with Elan to develop Fampridine SR, including preclinical studies [62, 63], studies to assess pharmacokinetics of intravenous [64], intrathecal [65], oral [66] 4AP in humans and animals [67].

In 2001, van der Bruggen, et al. [68] found that 4-AP (0.5 mg/kg) did not improve neurological function of 20 patients with chronic incomplete spinal cord injury.  However, 4-AP improved motor evoked potentials patients with chronic spinal cord injury [69] and Grijalva, et al. [70] randomized 27 patients to 4-AP or placebo, and found that 30 mg/day 4AP for 12 weeks improved neurological function in 69% compared to 46% on placebo. In 2004, Deforge, et al. [71] found no difference between 4-AP (40 mg/day) or placebo in 15 people who were walking after spinal cord injury.

From 2005 to 2007, after a phase 2 [72], more pharmacokinetics [73, 74] and safety trials [75], Acorda did two large randomized placebo-controlled phase 3 trials involving over 800 patients with chronic spinal cord injury to assess Fampridine SR effects on spasticity.  Both trials [not yet published] showed no significant difference between Fampridine SR and placebo.  However, Acorda also did two phase 3 clinical trials that showed that Fampridine SR significantly improves walking performance in multiple sclerosis (MS).

In summary, over a decade of clinical trials yielded promising and conflicting results concerning 4-AP effects on chronic spinal cord injury.  The trials surprisingly revealed that people with spinal cord injury are susceptible to placebo.  Over 40% of patients responded to placebo and perhaps half of the patients responded to 4-AP.  Until better outcome measures can be found, it may be better to choose a condition that is more responsive to 4-AP and go back later to demonstrate efficacy for spinal cord injury.

Nogo-A Antibody

In 1990, Schwab, et al. stunned the world with his study showing that IN-1, an antibody against an as-yet-unidentified myelin component [76], stimulates regeneration of rat corticospinal tract [77].  The first demonstration of a treatment that regenerates the spinal cord, the work convinced many neuroscientists that Aguayo and David [78-80] were right in their proposal that there is something about central myelin that stops axonal growth.  Unfortunately, the IN-1 antibody was promiscuous and bound to many proteins.  It took ten years before Schwab and his colleagues were able to isolate and clone the gene for the protein, now named Nogo [81-86].  With the purified protein finally available, Novartis licensed the patent for Nogo antibody treatment of spinal cord injury and embarked on an intensive program to develop the first regenerative therapy for spinal cord injury.

Many investigators tried different approaches to using the discovery of myelin-based growth inhibitory proteins to regenerate the spinal cord injury.  For example, Huang, et al. [87] reported that vaccinating mice with spinal cord may have induced antibodies that stimulated spinal cord regeneration, an approach that was later validated when the nogo protein itself was available to determine whether the vaccination induced the antibodies against nogo [88, 89].  If vaccination will induce antibodies that can stimulate spinal cord regeneration, this would be a very powerful approach indeed.

Novartis developed specific nogo-A antibodies that improve behavioral outcome and corticospinal plasticity in rats after experimental stroke [90], stimulated corticospinal regeneration in marmosets [91], increased plasticity in many different preparations [92-94].  After demonstrating that the antibodies penetrated into the spinal cord when infused intrathecally [95] and showing that the anti-Nogo-A antibody stimulated sprouting of corticospinal axons in macaque monkeys [96] and the treatment restores serotonin projections in rats after spinal cord injury [97], the Nogo-A antibody was taken to clinical trial in patients with chronic spinal cord injury.

The Novartis phase 1 trial of Nogo-A-antibody (ATI355) was recently completed.  The phase 1 trial (ClinicalTrials.gov identifier NCT00406016) was an open-label multicenter study to assess feasibility, safety, and tolerability of continuous infusing five doses of ATI355 intrathecally into patients starting 4-14 days after injury.  Paraplegic and ASIA A tetraplegic patients were included.  Tetraplegic patients who require artificial respiration could receive treatment as late as 60 days after injury, as soon as they were weaned off the respirator.  Patient with complete anatomical transection or obstruction of the spinal canal, multiple spinal cord lesions, cauda equina injury, brachial or lumbar plexus injury, significant head injury and systemic disease were excluded.  A phase 2 trial has started, indicating that the phase 1 trial has shown safety and feasibility.

In summary, the development of the Nogo antibody has taken nearly 2 decades since the initial discovery that that something in myelin inhibits spinal axonal regeneration.  The treatment has been validated in many laboratory studies and completed phase 1, indicating feasibility and safety.  Upcoming phase 2 trials will optimize the therapy and outcome measures, to be followed by pivotal phase 3 studies to show efficacy.

Cethrin

In 2001, Strittmatter et al. [98-107] described the receptor for Nogo.  The receptor, like many others that stop axonal growth and cellular migration, inhibits axonal growth by activating the intracellular messenger rho with rho kinase [108].  The Strittmatter laboratory identified a 66-amino acid fragment of Nogo that blocks the Nogo receptor [109-112] and other Nogo receptor blockers [113-124].  They even showed that MP and Nogo-66 have a synergistic effect on regeneration [125].  Working with Biogen, they subsequently found that the soluble Nogo receptor protein itself tightly bind molecules that inhibit axonal growth [123] and improves recovery after spinal cord contusion [126].

In the meantime, after studies of rho activation patterns in the spinal cord [127], Lisa McKerracher proposed [128] a new approach to target rho to stimulate repair and regeneration after spinal cord injury.  She used the bacterial toxin C3 to inhibit rho, modifying it so that it entered cells.  She formed the company Bioaxone to develop the drug.  The resulting cell-permeable recombinant protein BA-210 prevented secondary damage and promoted function recovery in spinal cord injury [129].  BA-210 or Cethrin subsequently went to phase 1 clinical trial [130, 131].  Bioaxone was recently bought be Alseres Pharmaceuticals (formerly Boston Life Sciences).

The Cethrin trial (ClinicalTrials.gov identifier NCT00500812) was a Phase I/IIa dose-ranging study to evaluate the safety, tolerability, and pharmacokinetics of BA-210 and the neurological status of patients following administration of a single extradural application of Cethrin during surgery for acute thoracic and cervical Spinal Cord Injury.  All the patients were ASIA A (complete).  Carried out from February 2005 to October 2008, the final data collection of the trial will be in June 2009.   The trial compared 0.3, 1, 6, and 9 mg of BA-210 applied to the dura surface of the injured spinal cord, during surgery that exposed the spinal cord for decompression.

Presentations of the Cethrin phase 1 trial results suggest possible beneficial effects of Cethrin in recovery after spinal cord injury [132].  Of 37 patients entered into the trial, they found no serious adverse side effects.  All the patients were ASIA A on admission.  The six-month patient data indicated that 28% of the patients (10 of 36) improved by one or more ASIA grades as compared to reported literature results of 6.7% [133].  Five of the patients improved to ASIA C and two improved to ASIA D.  One patient died form acute respiratory distress syndrome.

A phase 2 trial will start soon to evaluate the safety and efficacy of Cethrin in adult subjects with acute cervical spinal cord injury [134].   The trial is a randomized, double blind, placebo controlled study that will use mean ASIA motor score change as the primary outcome measure.  Six experimental groups will be compared:  placebo, 1 mg, 3 mg, 6 mg, 12 mg, and 18 mg Cethrin.  All the treatments will be applied epidurally during surgery exposing the spinal cord for decompressive or other purposes during the first several weeks after spinal cord injury.

Olfactory Ensheathing Glia (OEG)

The olfactory nerve is the only part in the central nervous system that continuously regenerates in adult mammals.  Its regenerative ability has been attributed to olfactory ensheathing glial (OEG) cells that are born in the nasal mucosa and migrate to the olfactory bulb.  Doucette [135] suggested that OEG cells would facilitate regeneration in other parts of the central nervous system, including the spinal cord.  In 1996, Smale, et al. [136] used OEG cells to repair transected fornix in the rat.  In 1997, Li, et al. [137] used OEG cells to repair adult rat corticospinal tract.  In 1998, Ramon-Cueto, et al. [138] reported that OEG transplants promoted regeneration in transected rat spinal cords.

In 2000, Barnett, et al. [139, 140] reported that human OEG cells can remyelinate axons.  Imaizumi, et al. [141, 142] used pig OEG cells to promote regeneration and remyelination in the spinal cord.  Ramon-Cueto, et al. [143, 144] reported functional regeneration in rats after spinal cord transection.  Many investigators enthused about the promise of OEG cells to bridge the gap in spinal cord injury [145-151].  One company (Alexion) grew OEG from genetically modified pigs as a substitute for human cells.

In 2001, Lu, et al. [152] reported that transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.  Shortly thereafter, in Portugal, Lima, et al. [153] began transplanting nasal mucosa into patients with chronic spinal cord injury and reported recovery of motor scores, as well as light touch and pinprick scores.  In total he transplanted nasal mucosa to over 160 patients with chronic spinal cord injury.  Several places, including Osaka University Medical School [154], want to continue the study.

In Brisbane, MacKay-Sim, et al. [155] successfully cultivated olfactory ensheathing cells from the nasal mucosa of 3 patients with chronic spinal cord injury and transplanted the cells into their spinal cords,  Compared with 3 patients matched for injury severity and other characteristics, the transplanted patients showed no adverse effects of the transplants. However, they also did not show any significant functional change or neuropathic pain at 3 years after the transplant.

In the largest published series to date, Huang, et al. [156] transplanted OEG isolated from olfactory bulbs of aborted fetuses into 171 patients with chronic spinal cord injury.  The patients showed significant increases in sensory scores but only modest improvements in motor function.  Dobkin, et al. [157] criticized the study, claiming that there were unreported complications and five patients did not show improvements.  Huang has denied these criticisms and published further studies suggesting that OEG transplants are safe and efficacious [158, 159].  He has transplanted OEG into over 1200 patients to date.

In summary, the discovery that OEG cells facilitate regeneration in animal spinal cords excited clinicians. Carlos Lima in Portugal transplanted autologous nasal mucosa into over 160 patients with chronic spinal cord injury with modest results.  McKay-Sim in Brisbane cultured nasal mucosa OEG cells and transplanted them into 3 patients who had no significant beneficial effects after 3 year.  Huang Beijing transplanted fetal OEG cells into more than 700 patients and find that they consistently restore significant sensory.

Human Embryonic Stem (HES) Cells

The 1977 disovery by Thomson, et al. [160] that pluripotent human embryonic stem (HES) cells can be isolated and cultivated indefinitely transformed stem cell research. The first study reporting efficacy of embryonic stem cells for spinal cord injury appeared in 1999 [172].  While several other cell transplants have reported to be beneficial for spinal cord injury, i.e. marrow stromal cells [162], fetal neural stem cells [163], and other cells [164-171], people thought that the only way to get cells for transplantation was to collect them from fetuses, blood, or bone marrow. HES cells can produce many cell types for transplants, including neural stem cells, which in turn can produce neurons, astrocytes, microglia, and oligodendroglia [161].

Geron helped fund the early work leading to the first successful cultivation of HES cells.  Working with Keirstead at UC Irvine [173-177], Geron has concentrated their attention on treating spinal cord injury with oligodendroglial progenitor cells derived from human embryonic stem cells [178-180].  However, after many announcements of clinical trials since 2005 [181], the first phase 1 trial of HES cells has not yet been approved by the FDA.

Many people assumed that the delays are due to opposition by the Bush Administration to clinical trials of HES cells in the United States, including a May 2008 hold by the FDA [182].  Some scientists are concerned that the first clinical trial of HES must be very carefully designed.  As Evan Snyder of the Burnham Institute pointed out, “The last thing we need is another Jesse Gelsinger, referring to the 18-year-old man who died during a gene therapy trial at the University of Pennsylvania in 1999.  After Gelsinger’s death, the FDA closed down many gene-therapy trials for several years.  Because it is the first time that human embryonic stem cells are being transplanted into human, the trial will be under a microscope and any adverse effect will be emphasized [183].

In statements to the public [184], Geron CEO Thomas Okarma has suggested that the company plans to study 40 people with acute spinal cord injury.  The trial will focus on patients who are “complete” (ASIA A) and within the first two weeks after injury.  It is not clear whether and how much immunosuppression will be used.  Geron scientists have reported that oligodendroglial cells differentiated from HES cells are not targets of innate and adaptive human effectors cells and are resistant to lysis by Neu5Gc antibodies [179]. However, Keirstead has suggeted that long-term immunosuppression may be necessary.

In summary, human embryonic stem cells have been the object of much hope and controversy.  Due to their pluripotency, many regard the cells to be a promising source of cells for transplantation.  Geron is one of the first companies to fund research leading to the first successful cultivation of human embryonic stem cells a decade ago.  The cells have not yet reached clinical trial stage. Geron chose to focus on spinal cord injury in their first clinical trials.  However, since 2005, despite repeated announcements, the first phase 1 trials have not yet been approved by the FDA.  The trial will likely study 40 patients with subacute spinal cord injury with oligodendroglial cells differentiated from a human embryonic stem cell line.  A major question is immune rejection of the cells and whether immunosuppression will be used.

Combination Therapies

Combination therapies achieve greater axonal growth than individual therapies [185].  To regenerate the spinal cord, therapies must address the following obstacles to regeneration.

  • Bridging the injury site.  The spinal cord injury site does not support regenerating axons for several reasons.  The injury site is disorganized, filled with inflammatory cells, lacks cellular adhesion molecules to guide axonal growth, and may contain factors the inhibit axonal growth.  Many laboratories are consequently transplanting cells or placing biomaterials to provide a bridge for axonal growth across the injury site.
  • Sustained source of growth factors.  Axons grow slowly, less than a mm a day.  They must grow long distances, as much as a meter, to reach their original targets.  To do so, there must be a sustained source of growth factors. Several neurotrophins, including NGF, NT-3, and GDNF are critical growth factors.  One way is to infuse the factors but a better way may be to stimulate either endogenous or transplanted cells to secrete growth factors.
  • Blocking growth inhibitors. Several factors block axonal growth in the spinal cord.  The best defined is the myelin-based factor Nogo.  Other include extracellular glycoproteins such as CSPG.  The former can be blocked by anti-Nogo-A antibodies, Nogo receptor blockers, rho inhibitors, and even soluble nogo receptor protein.  The latter can be digested by enzymes, including chondroitinase.

Individual therapies are being tested in clinical trials. To test combination therapies, we must have clinical trial networks that can test therapies rigorously and efficiently.  We have set up a clinical trial network to test spinal cord injury therapies in China.  Called the China Spinal Cord Injury Network (ChinaSCINet), this network currently has 25 centers in Mainland China, Hong Kong, and Taiwan, capable of randomizing many thousands of subjects per year.

ChinaSCINet is carrying out the first clinical trials of combination therapies of spinal cord injury, i.e. umbilical cord blood mononuclear cells (UCBMC) and lithium.  Many laboratories have reported beneficial effects of UCBMC on spinal cord injury [165-168, 170, 171, 186-188].  In 2004, Yick, et al. [189] reported that lithium stimulates regeneration in rat spinal cord. Subsequently, Su, et al. [190] found that lithium stimulates proliferation of neural stem cells in the spinal cord and Dill, et al. [191] showed that lithium promotes axon regeneration and recovery in rat spinal cord injury.

Lithium stimulates UCBMC cells to secrete NGF, NT-3, and GNDF and we therefore propose to carry out studies of lithium and UCBMC cells individually, in combination, and then with axonal growth inhibitor blockers such as anti-nogo-A antibody, nogo receptor protein, cethrin, and chondroitinase. UCBMC and lithium are attractive first therapies for clinical trial since both have been extensively used in humans for many years.  If UCBMC are effective, many cord blood banks are available to supply the cells.  Lithium is very low cost and can be taken orally.

Lessons Learned

What lessons have we learned from the above therapies for spinal cord injury?   Three lessons are clear:

  • Slow and Tortuous Process. Few therapies go through the development gauntlet without major hitches. The average time for therapy development exceeded a decade for all therapies described above. For example, development of MP required 13 years (1977 to 1990) from first preclinical discovery to NASCIS 2.  Weight-supported treadmill locomotor training required 14 years (1991-2005).  Fampridine (1987-now) and  Nogo-A antibody (1990-now) both are likely to take over 20 years to develop. The development of Cethrin began in 2003 and may complete clinical trials before 2013. OEG (1997-now) and embryonic stem cells (1997-now) both have taken over a decade already.
  • Rigorous proof-of-concept of treatment efficacy is required for companies, government, or foundations to invest millions of dollars into development of a therapy. In the case of companies, intellectual property protection is also necessary.  A large part of the development time for most of the therapies resulted from a prolonged period of research to establish proof-of-concept.  In certain cases, e.g. MP and locomotor training, the clinical trials and proof-of-concept research in animals proceeded in parallel.  However, both fampridine and nogo antibody therapies went through 10 years of extensive preclinical studies before the drugs was licensed.
  • Clinical Trials are Inherently Risky. A single mistake in clinical trial design can set a program by five or more years.  It is important to have systematic preclinical data before starting clinical trials.  For example, NASCIS 1 compared a ten-day course of 1000 mg/day and 100 mg/day without sufficient animal to indicate the optimal dose or timing of therapy, wasting over 5 years.  A wrong choice of outcome measures, such as the choice of spasticity as the primary outcome of the Fampridine trials added over five years to the development of fampridine for spinal cord injury.  Neither OEG nor HES cells have undergone any controlled clinical trials.

The development times for spinal cord injury therapies may have been particularly long because all of the therapies are the first in their class.  For example, MP was the first neuroprotective drug, weight-supported locomotor training the first major restorative rehabilitation treatment, fampridine was the first conduction enhancing drug, nogo antibody and cethrin are the first regenerative therapies, and OEG and HES transplants are both first of their class. Trailblazing is inherently time-consuming.

Clinical trial networks should reduce treatment development times because much time and expense of clinical trials must be spent on recruiting and train clinical trial centers. Having clinical trial networks that are ready and able to test therapies will not only improve the quality of clinical trials but should speed up and defray costs significantly. This will encourage companies to invest in spinal cord injury therapies.

Probability

How soon can we expect curative therapies of spinal cord injury?  To date, most spinal cord injury therapies have taken 10-20 years to complete clinical trials.  Establishment of clinical trial networks  and increased interest of pharmaceutical companies in spinal cord injury therapies may shorten the development time.  However, until significant new funding becomes available for spinal cord injury clinical trials, the rate of progress in developing therapies is unlikely to change significantly.

Fortunately, we are not starting from scratch and several promising therapies are already in the clinical trial pipeline.  Six of the 8 therapies described above are in or soon will be in clinical trials.  If each therapy has a 50% chance of success, we would have to be rather unlucky for all the trials will fail. In the case of 6 trials, the probability of all six trials failing is 1 in 64.  Clearly, it behooves us to have as many clinical trials going in parallel as possible.  The reason is that if one trial is successful, everybody wins.

The likelihood that a given clinical trial will be successful of course depends on the therapy and the amount of data supporting that particular therapy and clinical trial design.  If one rushes into a clinical trial without much preclinical data, one has a much greater risk of failure.  Since we have limited clinical trial funds and facilities, it would also increase the likelihood of successful clinical trials by focusing on those therapies that have the most supporting data.

The first successful clinical trial that restores function to people with subacute or chronic spinal cord injury will increase enthusiasm and funding for more clinical trials.  If any of the six therapies listed above, or dozens of therapies that are awaiting clinical trials, were to succeed, I believe that companies will begin investing in spinal cord injury therapies.   The first therapy is always the most difficult to get funded and moving.  Many of the therapies would also be the first of their classes, i.e. the first regenerative therapy, the first cell transplant therapy, the first remyelinative therapy.

Two types of clinical trial failures are harmful to the spinal cord injury community, the investigators, and the sponsors.  The first and worst are false negative trials, i.e. a trial that falsely indicates that treatment is ineffective, are particularly deleterious. Such trials may be underpowered, i.e. a trial that does not have enough subjects to establish significance.  It may also happen if the wrong outcome measure is chosen.  The second are inconclusive trials.  Inconclusive trials may result from poor followup and high drop out rates.

Finally, it is important to note that clinical trials that show that a treatment is ineffective are not “failures”.  Showing that a therapy does not work is just as important as showing that a therapy works.  It stops the waste of further time and resources on that particular therapy.  Thus, for example, many people believe that umbilical cord blood cells are beneficial for spinal cord injury.  In fact, several overseas clinics are offering and charging for umbilical cord blood treatment of spinal cord injury as if they have already been proven to be effective.  A rigorously conducted clinical trial that shows it is ineffective will stop wasteful practices.

Summary and Conclusions

Many people frequently ask how long it will take for a cure of spinal cord injury to be available.  In the last two decades, about a dozen therapies have gone to clinical trial.  To illustrate the course of therapy development, I described 8 therapies that have been through or are going into clinical trials for spinal cord injury.

  1. High-dose methylprednisolone (MP) is the first spinal cord injury treatment to be tested in a placebo-controlled randomized clinical trial.
  2. Weight-supported locomotor training is the first rehabilitation therapy that has been shown to restore function after spinal cord injury.
  3. Fampridine (4AP) is the first therapy that improves conduction in demyelinated axons but has not yet been shown to be effective in spinal cord injury.
  4. Nogo antibody is the first therapy shown to regenerate the spinal cord of rats and is currently in phase 2 clinical trials.
  5. Cethrin is a membrane-permeable recombinant bacterial toxin C3 that blocks rho, improves recovery in animals and humans, and is in phase 2 clinical trial.
  6. Olfactory ensheathing glia (OEG)  have been transplanted to >1200 patients with chronic spinal cord injury but has not yet been tested in a controlled trial.
  7. Human embryonic stem (HES) cells have been announced for clinical trial by Geron since 2005 and is still awaiting approval by the U.S. FDA.
  8. Combination therapies.  The China Spinal Cord Injury Network is now testing umbilical cord blood mononuclear cells and lithium alone and in combination.

The history of spinal cord injury therapy development teaches us three important lessons.  First, therapy development is slow and tortuous, with each therapy taking 10 or more years. Second, rigorous proof of concept is required before companies, government, or foundations will invest millions into developing a therapy. Finally, clinical trials are inherently risky.  A single mistake in trial design may set a program back by many years.

Development of curative therapies for spinal cord injury will require large clinical trial networks to test combination therapies systematically.  To regrow large numbers of axons across the injury site, therapies need to bridge the injury site with cells that support growing axons, provide a long-term source of growth factors, and block growth inhibitors in the spinal cord, as well as replace cells. We know that each of these is possible.

The China Spinal Cord Injury Network is beginning clinical trials of the first combination therapy: umbilical cord blood mononuclear cells and lithium.  Several groups had reported that cord blood cells are beneficial in animal models of spinal cord injury. Lithium enhances regeneration in the spinal cord, stimulates proliferation of cord blood cells and neural stem cells, and increases the production of neurotrophic factors.  If this combination is effective, we will add growth inhibitor blockers.

So, how long will it take?  Fortunately, we are not starting from scratch.  Six of the eight therapies described above are already in or will soon be in clinical trials.  Other therapies are achieving proof-of-concept and should reach clinical trial soon.  Even if each of these trials has only a 50% chance of success, the odds ratio that at least one will succeed in the next few years is high.  The time needed to develop curative combination therapies depends on funding and availability of clinical trial network.

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