Geron to begin stem cell trial for spinal cord injury

Hans Keirstead, UC Irvine

The FDA has lifted a clinical hold that has been in place since 2008 on Menlo Park, CA-based Geron's proposed trial for spinal cord injury. The multi-center phase I trial will be the world's first trial of a therapy based on embryonic stem cells.

In a press release, the company's president and CEO, Thomas Okarma, said:

"Our goals for the application of GRNOPC1 in subacute spinal cord injury are unchanged - to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient's injured spinal cord."

Alan Trouson, CIRM President, said:

“This is an important milestone for the whole field to have an embryonic stem cell therapeutic in clinical trials. We are looking with hope and expectation that the transplant will be safe and effective.”

The trial is based on work by CIRM grantee Hans Keirstead at UC Irvine. Prior to CIRM funding, his team matured embryonic stem cells into a form of neuronal cell called oligodendrocytes. When injected into rats with spinal cord injury, those cells protected the remaining spinal cord neurons and allowed the rats to walk.

In their press release, Geron described the reasons for the clinical hold:

The clinical hold was placed following results from a single preclinical animal study in which Geron observed a higher frequency of small cysts within the injury site in the spinal cord of animals injected with GRNOPC1 than had previously been noted in numerous foregoing studies.

In follow up work, Geron was able to prove to the FDA the safety of their stem cell product. The work directly leading to this clinical trial took place prior to the passage of proposition 71 to create CIRM. CIRM has funded follow-up work by Keirstead and others to improve on this potential therapy and expand the application of these cells to other diseases.

Here is Hans Keirstead discussing the long path from basic research to this clinical trial:





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Embryonic No More

CIRM grantees at UCLA have captured the first moment when an embryonic stem cell – it of infinite possibilities – chooses a more limited fate.

A press release from UCLA says the cell population (which the researchers dubbed human embryonic mesodermal progenitors, or hEMP cells) could be therapeutically useful. The cells still have broad ability to become bone, blood, muscle or blood vessels, but – and this is an important but – have lost the embryonic stem cell’s propensity to form tumors called teratomas.

Gay Crooks, a professor of pathology and laboratory medicine and senior author of the study, is quoted in the release as saying:

“The hEMP cells we isolated did not have the ability to make teratomas, so they should be a safer choice when thinking about developing therapies for use in humans.”

In addition to being useful in developing therapies, the cells are just plain cool. Scientists don’t know what it is that gives an embryonic stem cell the freedom to choose its fate (a state called pluripotency). Crooks puts it like this:

“We want to know what it is that switches on and off to make a pluripotent cell no longer be pluripotent. In this study, we found a cell population that can help us understand these processes, as it is such a close relative to embryonic stem cells, but has lost the ability to be pluripotent.”

What they learn could help colleagues who are looking for more efficient ways of reprogramming adult cells to become pluripotent iPS cells.

PNAS, July 19, 2010
CIRM Funding: Gay Crooks (RC1-00108-1)

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iPS and embryonic stem cells -- similar but not the same

Two papers in Nature publications have raised questions about whether reprogrammed adult cells, called iPS cells, are truly interchangeable with embryonic stem cells as many have been assuming. The papers found that iPS cells created from different adult tissues still bear some hallmarks of those starting blocks.

In a press release, George Daley, who was senior author on the Nature paper and is Director of the Stem Cell Transplantation Program at Children's Hospital Boston, said:

"iPS cells made from blood are easier to turn back into blood than, say, iPS cells made from skin cells or brain cells."

CIRM grantee Mahendra Rao at Life Technologies said in a story in The Scientist that iPS cells:

"are not truly similar to [embryonic stem cells] when examined at a high resolution.”

This work is generating such a stir because people have tended to think of iPS cells as the less controversial equivalent to embryonic stem cells. The same press release quotes the author of the Nature Biotechnology paper, Konrad Hochedlinger from the Massachusetts General Hospital Center for Regenerative Medicine, as saying that iPS cells do become more similar to embryonic stem cells the more times they divide in a lab dish.

On their blog, the Australian Stem Cell Centre wrote:

But what does this all mean for stem cell science? Ultimately findings such as these will help to improve reprogramming technologies. It also means that scientists need to be able to continue to work with and explore all of the different types of stem cells – iPS and embryonic stem cells derived from both donated IVF embryos and SCNT embryos. Limiting research by restricting access to certain cell types at this stage would severely impact progress towards using these cells to understand and ultimately treat disease.

This work comes after several papers showing some consistent differences between embryonic and iPS cells. We’ve blogged about that work here and here.

Nature, July 19, 2010
Nature Biotechnology, July 19, 2010
CIRM Funding: Jun Seita (T1-00001)

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Muscle stem cells a step closer to treating muscular dystrophy

Stanford scientists have overcome one significant hurdle in developing a therapy for muscle-wasting diseases like muscular dystrophy. Until now, the muscle stem cells that stand at the ready to repair muscle damage couldn’t be grown outside the safe confines of a muscle. Once uprooted from their home and transferred to a laboratory dish, they matured into less useful progenitor cells. That’s a problem because once mature the cells no longer have the potential to be transplanted to repair muscle damaged by injury or disease.

Until Helen Blau, CIRM grantee and Stanford”s Donald E. and Delia B. Baxter Professor, had a good idea, that is. According to a Stanford press release:

The researchers wondered if the way the cells are normally grown in culture could be the problem. After all, as Blau pointed out, cells are used to rubbing shoulders comfortably with their neighbors on all sides rather than being splayed out and anchored on a rigid plastic culture dish that is 100,000-fold less elastic than true muscle.

Blau and her team grew the cells on a hydrogel that mimicked the elasticity of muscle, and voila. In the Stanford press release Blau said:

“Clearly the cells grown on the more-elastic surfaces have better survival and self-renewing properties than those grown on standard tissue culture dishes. We conducted our experiments with muscle stem cells, but I expect this will be true for other types of adult stem cells as well.”

When transplanted into mice, the cells contributed to leg muscles, showing that the cells were not only more numerous but also therapeutically useful. The group said this discovery could pave the way for scientists to grow muscle stem cells in quantities needed for transplantation therapies to treat muscular dystrophy and other muscle diseases.

Science (Express Online) July 15, 2010
CIRM funding: PM Gilbert (TG2-01159); Helen Blau (RT1-01001)

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Blood Stem Cells Made Resistant to HIV

Researchers at the University of Southern California disrupted a gene in human blood-forming stem cells and made the cells resistant to infection by HIV. Equally important, the disruption of the gene HIV uses to invade cells did not alter the cells’ stemness; they were able to replicate as stem cells and differentiate into various blood cells. The latter is crucial for the goal of creating a long-term cure for AIDS that would allow patients to stop their medications.

The work seeks to replicate the situation of the “Berlin Patient” who appears to have been cured of both his HIV and lymphoma by receiving a bone marrow transplant of stem cells from a donor that had a naturally occurring mutation to the same gene, known as CCR5.

The researchers proved the genetically modified cells could resist HIV infection by injecting them into mice bred to tolerate human tissue. Those mice fought off infection and were able to produce new resistant blood cells.

In a press release from USC lead research Paul Cannon said:

“This hybrid of gene and stem cell therapy shows that it is possible to create HIV-resistant immune cells that can eventually win the battle against HIV in vivo.”

The team disrupted the CCR5 gene using a chemical trick called “zinc finger” technology developed by Sangamo BioSciences. In a press release the company said the approach:

“enables the permanent disruption of the CCR5 gene.”

Both Sangamo and Dr. Cannon are part of a $14.5 million CIRM Disease Team project that aims to move this work into human patients.

This video describes the work of the disease team:


The current research was published in the July 2, 2010 issue of Nature Biotechnology.

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Reducing teratoma risk from transplanted stem cells

By Paul Knoepfler

The two most serious obstacles to regenerative medicine therapies are potential immune rejection of transplanted cells and the possibility that such cells could form a type of tumor called teratoma.

CIRM grant recipient and professor of Biology at UC San Diego, Yang Xu, is tackling both of these hurdles. He and his colleagues have recently discovered a method to reduce the ability of embryonic stem cells to form teratoma. The approach involves interfering with the function of a key gene, called Nanog, that is involved in maintaining stem cells. Nanog is one of several genes known as plurpotency factors, which work together to keep cells in their embryonic state.

The paper describing this work, entitled “Phosphorylation stabilizes Nanog by promoting its interaction with Pin1”, was published this week in the Proceedings of the National Academies of Science. Xu and colleagues found that by inhibiting Nanog function in stem cells, those cells still formed teratoma, but they were only about one-third the size of tumors that formed by control cells.

Xu was quoted in a press release by UCSD as saying the method is only partially effective because “we are targeting only one pathway” and he speculates that targeting multiple pathways simultaneously might provide a more robust inhibition of teratoma formation.

Some important unanswered questions remain. Would inhibition of any key pluripotency factor, for example Oct3, produce the same effect? Are cells with reduced levels of pluripotency factors still able to give rise to normal differentiated cells of diverse types and in sufficient numbers to be useful for therapies? Could a similar effect be achieved by withdrawing growth factors, such as removing LIF from the media of mouse stem cells or FGF from the media of human stem cells?

Despite these remaining gaps in our understanding, this study provides an exciting foundation for improving the safety of regenerative medicine therapies, any area in the stem field that requires more attention.



PNAS, July 5, 2010
CIRM Funding: Yang Xu (RC1-00148)

Paul Knoepfler is assistant professor of Cell Biology and Human Anatomy at UC Davis School of Medicine. He publishes a blog about stem cell research.

Stem cells and preventive medicine

CIRM grantee and UC Davis stem cell scientist Paul Knoepfler has an important new entry on his blog: Five simple ways to protect your stem cells. In it he says:

If one can prevent a problem for occurring in the first place, it is far better than trying to treat it after the fact.

So true. Of course, many of the diseases CIRM scientists are involved in trying to treat aren't ones with known causes. We can't prevent our way out of all disease. But in the process of making discoveries to develop therapies, CIRM scientists are learning more about our own natural stem cells and how to keep them healthy. For example, exercise seems to fortify the neural stem cells that rebuild our brain.

Among his recommendations:

• Protect your skin stem cells
• Avoid plastics exposure
• Eat food, not chemicals
• Exercise
• Avoid radiation

So for the good of your stem cells get outside and exercise. But first, put on sunscreen.

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Cancer stem cells at the heart of melanoma

A team led by Irving Weissman at Stanford University School of Medicine has found the cancer-initiating stem cells in melanoma. Weissman has CIRM Comprehensive and Disease Team Awards relating to his cancer stem cell work.

According to a Stanford press release:

The finding is significant because the existence of such a cell in the aggressive skin cancer has been a source of debate. It may also explain why current immunotherapies are largely unsuccessful in preventing disease recurrence in human patients.

That's because any therapy that kills the bulk of the tumor without eliminating the cancer stem cells won't be effective:

Any therapy that doesn’t wipe out these elite cancer stem, or initiating, cells has no chance of completely eradicating the disease even if it destroys nearly all other tumor cells. That’s why, say proponents, it can be relatively easy to get a patient into remission, but extremely difficult to prevent the cancer stem cells from roaring back and causing a relapse months or years later.

The work was published in the July 1, 2010 issue of Nature.

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