Geron’s Oligodendroglial Precursor Cell Therapy Trial

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

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7 Responses to “Geron’s Oligodendroglial Precursor Cell Therapy Trial”

  1. 37 Says:

    Great Health News Here

  2. RC Says:

    Professor K has been working on potential stem cells treatments for the chronics. The Geron trial is based on an earlier work by the same Professor K for fresh contusion spinal injury. It has taken Geron years to get through the FDA approval process as it has to test a couple of thousand of mice on the purity of Geron’s cells. In the mean time Dr. K has done fund raising to support follow on research addressing chronic spinal injuries.

  3. Kataweb.it - Blog - diariotip » Blog Archive » Young sul trial Geron. Says:

    […] Rif.: wiseyoung.wordpress […]

  4. 52 Says:

    Great Health Resources Free…

  5. Wise Young Says:

    RC, I agree. Wise.

  6. Bob Katz Says:

    “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.” as stated by Media Savvy researcher Wise Young

    Wow, you sure through punches at a decent and worthwhile end3eavor while you can’t even admit some of the criticism of your methylprednisolone trial might be worthy! I though peer review was good, yet you hold on to MP after so many other researchers have found flaws.

    Maybe it is time to stop looking at already approved drugs like methylprednisolone or Lithium or non -controversial cells like cord blood, and you ain’t a hero for doing a chronis triaql, you sucking the sci communities money.

    I am a parent of an sci and I rake a strong dislike to you. You might fool the desperate ones, but you even coined a new logo, they ain’t desperate they are determined. It sucks we have you as our savioor, I feel you use us.

  7. joe ilaria Says:

    COULD I BENAFIT FROM THIS? I’M A “TBI” VICTIM FROM:1988. PLEASE CALL:1-(732)387-8701.A.S.A.P. THANK YOU !
    JOSEPH ILARIA

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