Stem cells treat Parkinson's disease in rats

CIRM grantees at the Buck Institute for Age Research have treated a rat version of Parkinson’s disease using transplanted cells that originated from iPS cells -- embryonic-like cells made from reprogramming adult cells. A press release from the Novato-based Buck Institute quotes CIRM president Alan Trouson as saying:

“The studies are very encouraging for potential cell therapies for Parkinson’s disease. The researchers showed they could produce quantities of dopaminergic neurons necessary to improve the behavior of a rodent model of PD. We look forward to further work that could bring closer a new treatment for such a debilitating disease.”

The group led by Xianmin Zeng created iPS cells from adult skin and blood cells. The group coaxed the cells to divide and produce a particular kind of nerve cell that is damaged in Parkinson’s disease, called dopaminergic neurons. They transplanted the neurons into rats with an induced form of Parkinson’s disease and saw symptoms diminish. The disease, which effects 1.5 million Americans, results in tremor, slowness of movement and rigidity

According to the press release:

The cells became functional and the rats showed improvement in their motor skills. Zeng said this is the first time iPSC-derived cells have been shown to engraft and ameliorate behavioral deficits in animals with PD. Dopamine-producing neurons derived from hESCs [human embryonic stem cells] have been demonstrated to survive and correct behavioral deficits in PD in the past.

In addition to showing that cells derived from iPS cells could treat symptoms of Parkinson’s disease, the group went one step farther. They also developed a way of creating the therapeutic cells that can be repeated in large quantities. That’s important because any therapy based on this work would require large numbers of cells.

“Our approach will facilitate the adoption of protocols to good manufacturing practice standards, which is a pre-requisite if we are to move iPSC’s into clinical trials in humans.”

Stem Cells, August 16, 2010
CIRM funding: Xianmin Zeng (CL1-00501-1)

Resting stem cells are cancer-prone

CIRM grantees at University of California, San Francisco, have published a Cell Stem Cell paper explaining why blood-forming stem cells accumulate cancer-causing mutations with age. Basically, they found that inactivity is genetically risky for the cells.

The blood-forming stem cells exist in the bone marrow where they divide periodically to form new cells of the blood system, including red blood cells, immune cells and platelets. When the cells are actively dividing they use a highly effective mechanism for repairing any damage to their DNA. The danger comes during the down-time. When the cells -- also called hematopoietic stem cells -- aren't dividing they use a less rigorous method for repairing DNA damage, which can be caused by radiation, drugs, or regular wear and tear.

In a press release from UCSF, the lead author Emmanuelle Passegué said:

“Our results demonstrate that quiescence is a double-edged sword, protecting hematopoetic stem cells from cellular stress but rendering them intrinsically vulnerable to mutagenesis following DNA damage.”

Passegue is associate professor of medicine (division of hematology/oncology) and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. She also received a CIRM New Faculty II Award, which funded this work.

A review that accompanies the paper says:

Because many hematopoietic disorders that stem from DNA damage accrual arise during aging, these results also stress the importance of examining DNA damage response and damage accrual during ontogeny and aging.

Cell Stem Cell, August 6, 2010
CIRM funding: Mary Mohrin (T1-00002); Emmanuelle Passegué (RN2-00934-1)

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Stem cells treat life-threatening skin condition

This week researchers at the University of Minnesota published a paper showing that stem cells from the bone marrow can help kids with a blistering skin condition called epidermolysis bullosa. The disease is horrible. Lacking a protein to anchor skin in place, the children's blister at the slightest touch -- on their skin, in their throat, inside their eyelids, and anywhere else skin forms.

The group gave the kids a bone marrow transplant, replacing their own blood system with cells that make the form of collagen lacking in kids with the disease. It worked. In a press release, John Wagner, M.D., director of pediatric blood and marrow transplantation and clinical director of the Stem Cell Institute, said:

“To understand this achievement, you have to understand how horrible this disease actually is. From the moment of birth, these children develop blisters from the slightest trauma which eventually scar. They live lives of chronic pain, preventing any chance for a normal life. My hope is to do something that might change the natural history of this disease and enhance the quality of life of these kids.”

A Canadian CBS news story quotes Pediatric dermatologist Dr. Elena Pope, medical director of the EB clinic at Toronto's Hospital for Sick Children, as saying:

"It's extremely, extremely exciting for us who are working in this area to actually see some steps forward."

CIRM funds a disease team headed by Alfred Lane at Stanford Univerversity, who is also working toward a stem cell-based therapy for the disease. His team is creating reprogrammed iPS cells from the children's skin, inserting a good copy of the mutated gene, and transplanting the resulting skin cells back onto the children. 

CIRM's epidermolysis bullosa disease team: Anthony Oro,
Gerhard Bauer, Alfred Lane, Marius Wernig

Whichever approach is successful long-term, it's nice to see progress being made for this truly horrible disease. 

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Mouse muscles mimic newt regeneration

A disclaimer: this work was not funded by CIRM, nor does it directly have to do with stem cell research. It is, however, extremely cool, and strikes close to home. I spent hours as an undergrad slicing off the limbs of newts and marveling as the tiny fingers and toes re-emerged on newly formed limbs. Now Helen Blau at Stanford University has for the first time replicated that magic in mammals.

In a Stanford press release, Blau is quoted as saying:

“Newts regenerate tissues very effectively. In contrast, mammals are pathetic. We can regenerate our livers, and that’s about it. Until now it’s been a mystery as to how they do it.”

Admittedly, the group didn’t regrow entire mouse limbs. What they did is prod mouse muscles to divide — something that mammalian muscles don’t generally do, and that needs to happen in order to form working limbs. It turns out that two genes normally required to prevent cancer also prevent muscle cells from dividing. Temporarily blocking those genes returned the muscles to a dividing state. As the press release makes clear, the key is “temporarily”:

As is clear from the mouse experiments, blocking the expression of tumor suppressors in mammalian cells can be a tricky gambit. Permanently removing these proteins can lead to uncontrolled cell division. But, a temporary and well-controlled loss — as the researchers devised here — could be a useful therapeutic tool.

Nicholas Wade wrote about the work in the New York Times:

Jeremy Brockes, a leading expert on regeneration at University College London, said the report was “an excellent paper.” Though there is a lot still to learn about the process, “it is hard to imagine that it will not be informative for regenerative medicine in the future,” he said.

Although CIRM didn’t fund this work, Blau does have a Tools & Technologies award and a Basic Biology I award. She’s featured in this recent blog entry about her CIRM-funded work.

Cell Stem Cell, August 6, 2010

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Fibroblasts reprogrammed to heart cells

Cardiac muscle (red) with reprogrammed
fibroblasts (green). Srivastava lab.

The dogma was once that mature cell types like skin or nerves needed to be reprogrammed to an embryonic-like state before they could mature into a different cell type. Essentially, if a cell was a doctor it would need to go back to kindergarden before it could grow up to become a lawyer.

That was until last year when Doug Melton and his team at the Harvard Stem Cell Institute did the equivalent of sending the cellular doctors directly to law school. They succeeded in converting one type of mouse pancreatic cell directly into the pancreatic beta cells that produce insulin. Earlier this year, Stanford scientist Marius Wernig carried out a similar feat, turning skin cells into nerve cells.

Now another CIRM grantee — this time Deepak Srivastava at the Gladstone Institute of Cardiovascular Disease and UCSF — has bypassed the embryonic state. He reprogrammed mouse fibroblasts directly into primitive heart cells. In a press release, Srivastava said:

“The ability to reprogram fibroblasts into cardiomyocytes has many therapeutic implications. Half of the cells in the heart are fibroblasts, so the ability to call upon this reservoir of cells already in the organ to become beating heart cells has tremendous promise for cardiac regeneration."

This work builds on work by another Gladstone scientist. Shinya Yamanaka was the first to reprogram adult cells to an embryonic state called induced pluripotent stem (iPS) cells. What Srivastava, Wernig and Melton have shown is that this initial reprogramming step may not always be needed to create therapeutic cell types. Avoiding the embryonic state may avoid the tumor-causing potential of embryonic cells and may have other advantages, according to the Gladstone release. However, Srivastava points out that this cellular career switch has yet to succeed in human cells.

Cell, August 5, 2010
CIRM Funding: Deepak Srivastava (RC1-00142-1), Benoit Bruneau (RN2-00903-1)

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The competition that isn't: Adult vs. embryonic stem cells

The past few days have sent the blogosphere -- especially the anti-embryonic stem cell blogosphere -- abuzz over a story by the Associated Press with the headline "Adult Stem Cell Research Far Ahead of Embryonic."

It's true. At this time there are many adult stem cell trials and only one embryonic stem cell trial underway. But what the story makes clear, if you read past the headline, is that adult stem cells were first out of the gate and are therefore first to trial. The story does highlight several of the exciting applications of adult stem cells. What it doesn't do is suggest that embryonic stem cells aren't of value.

Consider this: Irv Weissman of Stanford University (and multiple CIRM grantee) discovered the first adult stem cells in the bone marrow of mice in 1988. Ten years later, James Thomson of the University of Wisconsin created the first human embryonic stem cells.

With that timeline in mind, the AP story quotes Hank Greely, Stanford law professor and long-time follower of stem cell research, as saying:

"Give it another five years and I'll be surprised if we don't have some substantial progress" beyond the initial safety studies of embryonic stem cell research.

CIRM funds both adult and embryonic stem cell research. That's because at this stage of the research it's too early to know which cells will be the best therapeutic option for different diseases and conditions. In fact, many of the very people leading adult stem cell trials (including Weissman) advocate also pursuing embryonic stem cell research and have signed an open letter endorsing all forms of stem cell research. You can look up names of researchers who have signed here. Many of those names will be familiar as adult stem cell researchers in the AP story.

Those who oppose embryonic stem cell research are quick to appoint the first stem cell discovered as the leader. But in this case first doesn't mean best, and we won't know which cell type is best for many years. In fact, the best cellular therapy may depend on the disease -- adult cells for one disease, embryonic for another, and small molecules discovered through stem cell research for still other diseases.

At CIRM, we're excited about all potential therapies to end chronic disease and injury. Some of those therapies may come from adult stem cells. Others may come from embryonic stem cells or reprogrammed iPS cells. Whatever the origin of the cellular therapy, CIRM hopes that by funding all avenues of stem cell research we will push the field ever closer to the best therapies for disease and injury.

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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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