Alzheimer's leader discusses stem cell progress

Tom Vasich at the University of California Irvine did a Q&A with CIRM grantee Frank LaFerla in advance of the September 30 Southern California Alzheimer’s Disease Research Conference. La Ferla and his colleagues have been working on stem cell-based therapies for Alzheimer's disease.

In a question about the public health impact of Alzheimer's disease LaFerla said:

It’ll be enormous, especially locally. California has the nation’s largest baby boom population; Orange County by itself ranks fifth. Alzheimer’s is going to hit us hard, because age is the most significant risk factor for the disease. One of every 20 people over 65 will be affected by dementia, and eventually half of those over 85 will suffer from Alzheimer’s. This is going to put an amazing strain on our healthcare system and on families.

He went on to talk about his own research, funded by CIRM:

We’ve had a lot of success with animal models showing that neural stem cells can reverse Alzheimer’s-like cognitive deficits. We’ve progressed to creating a population of human neural stem cells that will be the basis of clinical trials on patients. We’re still in the early stages, and we’re fortunate to have received a grant from the California Institute for Regenerative Medicine that is supporting our work.

We had the pleasure of talking to LaFerla about this week a few years ago. In this video, he describes the work and the importance of finding a therapy for the disease.



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CIRM grantee Alvarez-Buylla wins 2011 Prince of Asturias Award for neural stem cell research

Arturo Alvarex-Buylla, PhD

CIRM grantee and UCSF professor Arturo Alvarez-Buylla, PhD, won the prestigious 2011 Prince of Asturias Award for Technical and Scientific Research for his work with neural stem cells. He is credited with first discovering the regenerative cells in the brains of mammals, work that laid the groundwork for a number of CIRM grants and clinical trials based on neural stem cells.

In their announcement about the award UCSF quotes Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

“Arturo’s contribution to the field of adult stem cell science has been tremendous. He has helped lay the foundation for our understanding of the role and behavior of neural stem cells in the adult brain, which could lead to new strategies for treating brain damage and diseases.”

In the announcement, Jennifer O'Brien describes the work that earned Alvarez-Buylla his recognition:

Alvarez-Buylla, specifically, was recognized for identifying neural stem cells in the brains of mammals, and for his ongoing research on their behavior – and potential therapeutic use – in treating diseases. He is exploring their possible role in the development of the most common type of brain tumor, the glioma, and their potential use in regenerating brain tissue damaged by injury or degenerative diseases. More generally, he is studying the way in which adult neural stem cells behave and function – their development into young neurons, the migration of these neurons from their site of birth to their final destinations, and their function in the adult brain.

Alvarez-Buylla has a CIRM Early Translational II Award to develop a cell-based therapy to inhibit the hyperactive neural circuits in people with epilepsy. In his public summary for the award he writes:

In 20-30% of these patients, seizures are unresponsive to drugs, requiring invasive surgical resection of brain regions with aberrant activity. The candidate cells we propose to develop can inhibit hyperactive neural circuits after implantation into the damaged brain. As such, these cells could provide an effective treatment not just for epilepsy, but also for a variety of other neurological conditions like Parkinson's, traumatic brain injury, and spasticity after spinal cord injury.

It's great to see CIRM grantees honored for the incredible advances they've in medicine and human health.

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Gene replacement in stem cells made easier

A press release about CIRM grantees at the Salk Institute for Biological Studies contains what might be the truest words in stem cell science:

In principle, genetic engineering is simple, but in practice, replacing a faulty gene with a healthy copy is anything but.

Several CIRM grantees could sum up their work in that same way. We've funded a variety of projects that all intend to replace faulty genes in stem cells with healthy ones, and then use the tricked-up stem cells to treat disease. That's how both of our HIV/AIDS disease teams hope to conquer HIV infection and also underlies our sickle cell disease and epidermolysis bullosa teams. (A list of disease teams with links to their research summaries is available here.)

The Salk researchers have published a paper in Cell Stem Cell describing a new way of replacing a gene with a therapeutic version. As a model, they used stem cells they had reprogrammed from a person with a genetic premature aging condition called Hutchinson-Gilford progeria. That condition is caused by a mutation in a gene called Lamin A. They used the technique to replace the defective Lamin A in the reprogrammed stem cells with a healthy copy of the gene. According to postdoctoral researcher and co-first author Guang-Hui Liu:

"The process was remarkably efficient and we couldn't detect any undesired off-target effects such genomic instability or epigenetic abnormalities," says Liu. "What's more, it allowed us to show that we can correct multiple mutations spanning large genomic regions."

The group also showed that their technique worked in mesenchymal stem cells, which are a form of tissue-specific stem cells many groups are also using to develop therapies.

The issue of being able to swap out defective genes is just one of many hurdles for scientists developing stem cell-based therapies. These behind-the-scenes issues rarely make the newspapers and remain largely invisible to the people who are waiting to see those future therapies, but are an active area of research for CIRM grantees. Hopefully work like this will help eliminate those hurdles and speed the path to the clinic.

Cell Stem Cell, May 19, 2011
CIRM Funding: Jeanne Loring (TR1-01250), Guang-Hui Liu (TG2-01158)

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Eradicate cancer stem cells, eradicate drug-resistant leukema

Markus Müschen/UCSF

CIRM grantees at the University of California San Francisco have found the protein certain leukemia cells use to evade chemotherapy. A press release from UCSF says:

Doctors who treat children with the most common form of childhood cancer – acute lymphoblastic leukemia – are often baffled at how bulk cancer cells die from chemotherapy whereas the rare stem cells in cancer survive their best efforts and the most powerful modern cancer drugs. Months after a seemingly successful treatment, the cancer stem cells re-initiate the disease, which is then more resistant to treatment than before.

It turns out the resistant cancer stem cells make a protein called BCL6, which protects them from the effects of chemotherapy. In a Nature paper published today, the team tested an experimental drug called RI-BPI, which attacks cells that make BCL6. Combined with the drug Gleevac, which is very effective at destroying the non-BCL6 cells, the experimental drug could effectively cure mice with drug resistant leukemia. In the release, CIRM grantee and senior author Markus Müschen said:

“We believe this discovery is of immediate relevance to patient care.”

In the work reported in this paper, the team used a molecule to block BCL6 that, though effective for small scale use, would be difficult to mass produce. Müschen has a CIRM Early Translational II Award to develop a drug that is similarly effective at destroying drug-resistant leukemia cells but that would be easier to mass produce for widespread use.

We have more information about cancer stem cells on our website:

• Leukemia information
• Cancer stem cell video

Nature, May 18, 2011
CIRM Funding: Markus Müschen (TR2-01816)

iPS cell smack down

Pity the iPS cell -- it's had quite a ride this year. On the upside, cells reprogrammed from people with autism, Parkinson's disease and schizophrenia were used to create the first ever models of those diseases in a dish. Those models could provide a way of testing drugs on actual human cells. That's good.

But in the same year, a number of studies found significant genetic differences between reprogrammed iPS cells and their embryonic counterparts (here's our blog entry). Today, a paper published in Nature by CIRM grantee Yang Xu at the University of California, San Diego found that the cells can also be rejected by the body.

This finding is a bit of a blow. When Shinya Yamanaka and colleagues first reprogrammed human skin to an embryonic-like state in 2007 the stem cell world was aflutter. These cells were seen by some as a possible replacement for embryonic stem cells, with the advantage that because they could be generated from a person's own skin they would be genetically identical and not get rejected by the immune system.

It turns out the immune system is smarter than that, at least in mice. The mice were able to detect and subsequently reject genetically identical iPS cells.

A New York Times story quotes George Daley of Boston Children's Hospital:

“As with any new technology, there is always this initial phase of infatuation, and then the reality sets in,” said Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital Boston. “I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.”

Apparently what made the cells visible to the immune system were the genes that were activated in order to reprogram the cells. The immune reaction varied depending on how the cells were made. This work isn't exactly the death knell for iPS cells, but it does mean that the path to the clinic could be a tricky one.

May 13, Nature
CIRM Funding: Yang Xu (TR1-01277)

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California/Scottish collaboration to heal bones

The good folks at the Scottish Stem Cell Network have pointed out an interesting relationship between CIRM and Scotland. We don't have a formal funding relationship with Scotland (you can read about our collaborative funding agreements here) but we do have a researcher with a foot in both countries.

Bruno Péault is Professor and Chair of Vascular Regeneration at the University of Edinburgh and holds a joint appointment at the David Geffen School of Medicine at UCLA. He has an Early Translational II Award to develop ways of harnessing stem cells in blood vessels to repair bone damage. The CIRM award only funds the portion of the research taking place in California.

According to the SSCN profile, Péault is in the process of setting up an exchange program between the two universities, ensuring that stem cell expertise crosses borders. They write:

Fueled by this grant and strongly supported by both Californian and Scottish Universities, this collaboration is aimed to develop in other research directions, notably ongoing studies related to normal and leukemic blood cell formation and development.

The profile was written as part of Scotland Week, which the SSCN celebrated with a series of profiles about stem cell research collaborations including Scottish scientists. In case you missed it, kilt day was Wednesday. No word on when bagpipe day was, but I'm pretty sure Friday might be scotch night at my house.

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Reflecting on muscular dystrophy awareness week

This past week was muscular dystrophy awareness week, which seems like a short amount of time to focus on such a heartbreaking disease. One in every 3500 boys in the US develops that debilitating and fatal Duchenne muscular dystrophy (DMD) - the most common and serious form of muscular dystrophy - and there is no cure.

CIRM funds a few awards to researchers studying the muscle stem cells called satellite cells. These dot the muscle fibers, ready to spring to action when there’s damage. In kids with MD, those satellite cells can’t repair the damage and the muscles eventually waste away.

Here’s a list of CIRM-funded projects that could lead to new insights or therapies for MD. One Early Translational II project to Michele Calos at Stanford University is especially interesting. Starting in mice, she’s proposing to reprogram cells from animals with MD, fix the defective gene, then grow those cells into muscle stem cells that can be transplanted back into the mice. If the technique works, she and her team hope to start working with human cells.

As with all early research there are a lot of unknowns. Can they actually fix the gene? Can they grow up enough muscle stem cells for transplantation? Will those manipulated cells thrive and be able to repair the damaged muscle? And a big question: How on earth do you get those genetically altered cells to all the wasted muscles in the body?

Hopefully in future muscular dystrophy awareness weeks we’ll be able to answer some of those questions, and one day if all goes well we’ll be writing about a cure.

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Protein Aids Bone Healing

At the intersection of stem cell research and the world of Harry Potter you'll find new work by CIRM grantees at Stanford University School of Medicine that can speed the rate of bone healing by three times. It's not quite Skele-gro, but it's close, at least in mice.

The research is based on a protein called Wnt that was long-known to be involved in the growth of many kinds of tissues and in the differentiation of stem cells. What's new is that the researchers managed to package the Wnt in a form that allows it to be delivered directly to tissues that need it. In a press release, senior author Jill Helms said:

“We believe our strategy has the therapeutic potential to accelerate and improve tissue healing in a variety of contexts.”

Helms and her collaborators delivered the packaged Wnt into the bones of mice with an induced injury. After 28 days, those mice had completely healed while the bones of their untreated lab-mates were still in the repair process. It appears that the Wnt triggers progenitor cells in the bone to multiply and heal the wound. Helms thinks the approach could be useful for healing tissues in addition to bone:

“After stroke and heart attack we heal the injuries slowly and imperfectly, and the resulting scar tissue lacks functionality. Using Wnt may one day allow us to regenerate tissue without scarring.”

From Stanford's blog Scope:

NatureNews also reported on the study, which appears in the journal Science Translational Medicine, and quoted a Columbia University expert who called the work "a major technological advance." But developmental biologist Roel Nusse, PhD, stressed there is still a lot of work to do.

This research marks the 500th paper published with CIRM funding.

Science Translational Medicine, April 28, 2010
CIRM funding: TR1-01249

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Small DNA changes, life or death consequences

Two recent papers by CIRM grantees highlight the importance of understanding basic stem cell biology while developing new cures. Both have to do with chemical modifications to the DNA – called epigenetics.

One of the two papers shows that an epigenetic change in DNA, called methylation, changes dramatically as human embryonic stem cells mature into specific cell types; the other shows that even subtle DNA methylation differences alter the way a cell behaves.

The first paper, by Jeanne Loring at The Scripps Research Institute, working with scientists in Singapore and New York, provides detailed maps of DNA methylation over the entire 3 billion “letters” that make up our DNA. By comparing methylation patterns of human embryonic stem cells and more mature cells, the scientists tracked the large number of epigenetic changes, many of them surprises, that occur when cells differentiate.

A press release quotes first author Louise Laurent as saying:

"The data are publicly available, and we are looking forward to learning what other scientists discover from using this information for their own studies on individual genes, embryonic development, and stem cells."

The second paper, from UCLA, focuses on epigenetic differences in pancreatic cancers, showing that differences in these modifications translate to different responses to chemotherapy. This means that a few DNA modifications here or there could mean life or death.

In a press release the authors say the next step is to develop a test doctors can use to figure out which patients will respond well to standard chemotherapy and which need an alternative treatment.

Taken together, the papers make a compelling case for how basic biology research such as understand DNA modifications can inform scientists who are actively pursuing cures.

Genome Research, February 4, 2010
CIRM funding: Jeanne Loring (RT1-1108 and TR1-01250)

Journal of Clinical Oncology, February 8, 2010
CIRM funding: Siavash Kurdistani (RN1-005505)

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