CIRM grantees convert skin to nerve precursors

A new paper from grantees at Stanford University School of Medicine reports an advance in directly converting one adult cell type to another. This paper, out of Marius Wernig’s lab, builds on his previous work converting mouse skin cells and then human skin cells into nerve cells.

In recent years, a handful of researchers have managed to convert on adult cell type direct into another mature cell type, bypassing the need to reprogram the cells to an embryonic-like state. This technology is still a long way from being ready for therapies (as you can read about in our blog here). Still, the technique suggests the possibility of one day directly converting a cell in the body into a type that's needed to repair damage, or of creating replacement cells in the lab.

In this latest installment, Wernig and his group converted mouse skin cells into a precursor to nerves called the neural precursor cell. This may sound like a relatively small difference over previous work, but the implications are big.

A press release from Stanford describes this advance:

This new study, which will be published online Jan. 30 in the Proceedings of the National Academy of Sciences, is a substantial advance over the previous paper in that it transforms the skin cells into neural precursor cells, as opposed to neurons. While neural precursor cells can differentiate into neurons, they can also become the two other main cell types in the nervous system: astrocytes and oligodendrocytes. In addition to their greater versatility, the newly derived neural precursor cells offer another advantage over neurons because they can be cultivated to large numbers in the laboratory — a feature critical for their long-term usefulness in transplantation or drug screening.



In the study, the switch from skin to neural precursor cells occurred with high efficiency over a period of about three weeks after the addition of just three transcription factors. (In the previous study, a different combination of three transcription factors was used to generate mature neurons.) The finding implies that it may one day be possible to generate a variety of neural-system cells for transplantation that would perfectly match a human patient.



“We are thrilled about the prospects for potential medical use of these cells,” said Marius Wernig, MD, assistant professor of pathology and a member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “We’ve shown the cells can integrate into a mouse brain and produce a missing protein important for the conduction of electrical signal by the neurons. This is important because the mouse model we used mimics that of a human genetic brain disease. However, more work needs to be done to generate similar cells from human skin cells and assess their safety and efficacy.”


Back in July we blogged about Wernig’s work and the time it takes to turn these types of advances into new therapies. (You can read that blog here.) We’ve also written about related work by CIRM grantee Deepak Srivastava, who is director of cardiovascular research at the Gladstone Institutes at the University of California-San Francisco (here’s more on his work). Stanford quotes Srivastava commenting on Wernig’s work:

“Dr. Wernig’s demonstration that fibroblasts can be converted into functional nerve cells opens the door to consider new ways to regenerate damaged neurons using cells surrounding the area of injury. It also suggests that we may be able to transdifferentiate cells into other cell types.”

CIRM funding: Ernesto Lujan (TG2-01159)

A.A.

Lujan, E., Chanda, S., Ahlenius, H., Sudhof, T., & Wernig, M. (2012). Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1121003109

Guest blogger Alan Trounson — January’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

This month’s review has to start by noting a key milestone for the field: the first published data from a clinical trial using cells derived from embryonic stem cells (ESCs). This Lancet paper from UCLA and Advanced Cell Technologies (ACT) describes results from a trial testing a potential therapy for two causes of blindness. The fact that two patients in the trial showed some preliminary improvements in vision created a historical timeline marker for the field. The date 1-23-12 can now go up alongside 3-09-09, the date President Obama lifted federal restrictions on ESC funding.

However, you must remember that this latest milestone is based on very limited, preliminary data. It involved only two patients and its suggestions of safety and potential benefit are based on following those patients for only four months. Many more patients and more follow-up data are needed, as my colleague blogged about here.

Another paper this month on eye disease provides a great example supporting CIRM’s philosophy of funding all types of stem cells because you never know which ones will work most effectively for which patients. Where the UCLA/ACT team was using embryonic stem cells to derive the retinal pigment epithelial (RPE) cells that are degraded in macular degeneration, a New York team isolated cells from the RPE of cadaver eyes that were able to revert to a stem cell state when placed in culture. The team was then were able to redirect those cells to create an RPE monolayer like the one that naturally occurs in the eye. Although they used donor tissue, these cells exist in everyone and could be harvested by needle biopsy from a patient. This theoretically could give patients replacement tissue that matches their own and would not raise issues of immune rejection.

You can read more about macular degeneration and CIRM's grants targeting blindness on our website.

Even though I have discussed disease-in-a-dish models from reprogrammed iPS cells several times in this blog, I can’t resist mentioning one more. A recent Nature paper cites three CIRM comprehensive grants and one training grant, and several of the authors are now housed in the Sanford Consortium for Regenerative Medicine building, constructed in part through CIRM funding. In that paper, the researchers reprogrammed skin cells from people with Alzheimer’s disease then matured those stem cell into nerves. (We blogged about that work here.) It makes major strides in understanding the cellular basis for Alzheimer’s disease and points to opportunities for earlier diagnosis and to potential avenues to therapy.

My full report of this month’s highlights is here.

A.T.

Genomics and stem cell research give patient her life back

Sandra Dillon and her fiancé at the CIRM governing board meeting. Thanks to board member Leeza Gibbons for the photo.

Todd Dubnicoff is CIRM’s videographer and video editor

At 28, Sandra Dillon was the picture of healthy living. She ran every day, ate healthy, didn’t smoke and recycled. But she had been bothered by a bump under her rib cage and after numerous tests, her doctors came back with very bad news: she had myelofibrosis, a life-threatening blood disorder that can lead to acute leukemia. No cure existed and no match for a bone marrow transplant was found. The only course of treatment was to try to manage her symptoms as she got sicker. Basically, there wasn’t much hope.

That was eight years ago. Flash forward to last week when Dillon spoke at the CIRM Governing Board’s Spotlight on Disease seminar (watch that video on our website or on our YouTube Channel CIRMTV) to happily report a more hopeful prognosis now that she’s participating in a clinical trial that targets cancer stem cells:

I’ve been on this trial for almost three months and my spleen is getting smaller…This is after eight years…of perpetual pain like I was stuck at the top of a mountain where there wasn’t enough air and I couldn’t acclimate…I felt exhausted constantly and now I have energy.

Dillon’s story provides a glimpse into a future of personalized medicine in which genomics, the study of genes and their function, is applied to pinpoint specific treatments for patients. Catriona Jamieson, Sandra’s physician and director for stem cell research at the UCSD Moores Cancer Center, spoke about the research, funded in part by CIRM, which led to the clinical trial. Using patient samples and leukemia stem cells, Jamieson’s team identified abnormal gene activity responsible for the cancer progression. A specific small molecule known to inhibit this mutant gene activity halted the disease.

Craig Venter, a leading expert in genomics and president of the J. Craig Institute, also spoke at the Spotlight and described personalized medicine this way:

Knowing your genetic code, knowing your genetic variation is part of the future of medicine and part of determining whether you’re going to be treatable by existing drugs.

Application of genomics will be essential for developing stem cell therapies in addition to drug development based on lessons learned from stem cells in the lab. Both Venter and Jamieson point out that merely growing stem cells in the lab introduces changes in their genetic code. These changes can lead to genomic instability, which is associated with cancer. So it will be very important to understand these changes, why they happen, and how to prevent or repair them. Venter stressed this point with a prediction:

I’ll go as far to say that there will be no clinical stem cell application without understanding the genomics and the genetic variation that takes place to ensure we don’t do more harm than good.

The importance of genomics is not lost on the CIRM governing board. Later in the afternoon after the Spotlight, the board approved a $40 million CIRM Genomics Initiative to give California researchers the opportunity to access genomics tools to better understand the stem cells they are working with and to help advance those cells toward therapies for patients. (We blogged about that initiative here.)

Sandra Dillon also appreciates the importance of genomics. Before she began her clinical trial, she was in too much pain and too exhausted to go out with friends at night. Now she plans to stay out all night with her fiancé during their wedding in March.

This page has more information about the work of CIRM grantees developing therapies for leukemia.

T.D.

Alzheimer's disease in a dish provides hope, avenue to therapies

In Lawrence Goldstein’s lab at the new Sanford Consortium building in San Diego, a series of lab dishes hold cells that could unlock some of the mysteries of Alzheimer’s disease.

These cells are neurons made from the skin of people who have the disease. Goldstein and his team reprogrammed those skin cells into embryonic-like iPS cells, then matured those into nerve cells. The nerve cells in the dish show many of the same abnormalities scientists have come to recognize as hallmarks of the disease – higher levels of some proteins that form tangled masses and plaques in the brain.

The work was published today in Nature and is based on funding from CIRM awards to Goldstein and his co-authors Martin Marsala, Fred H. Gage and first author Mason Israel.

In the past, those tangles and plaques have only been seen in biopsies taken from people with the disease after they have died, providing a snapshot of the ravages caused by a lifetime of the disease. These cells and their unusual proteins in the lab dish represent the first time scientists have been able to study how the human nerve cells first start to go awry, and could provide clues to help guide new treatments for the disease. Currently there are no drugs to treat the estimated 30 million people worldwide who have the disease.

A story in Nature describes the work:

Scientists aiming to learn the causes of Alzheimer’s have looked to brain biopsies of patients after they die, blood tests and animals as diverse as fruitflies and fish. Until recently, it has not been possible to probe the neurons of Alzheimer’s patients before they show symptoms.

“By the time you can see dementia in a person, their brain cells have been behaving in an abnormal way for years, perhaps decades or longer,” says Larry Goldstein, a neuroscientist at the University of California, San Diego, who led the study published online today in Nature.

The group started with skin cells from four people with Alzheimer’s disease, two with the disease in their family and two who did not have the disease in their family. The idea is that the disease runs in families due to a single genetic change that makes the cells malfunction. The people who don’t have the disease in their family might have developed the disease due to genetic or environmental causes or other reasons. Having both sets of cells could allow the researchers to tease apart how the disease originates in people with known mutations versus through other causes.

These kinds of disease-in-a-dish studies have been carried out for a few different diseases in recent years, including schizophrenia, Parkinson’s disease and forms of autism, among others. In each case, one goal is to use the cells to test for drugs that can eradicate symptoms. If a drug can return an Alzheimer’s-like cell in a lab dish to a normal state, it might also help treat a person with the disease.

Nature writes:

But the hope is that such cells will help scientists to develop new drugs and match them to individual patients based on how their reprogrammed brain cells respond. Reprogrammed cells could even be used to diagnose people with Alzheimer’s decades before they show symptoms, Goldstein says. This would be of little use without proven therapies, but early diagnoses could help scientists select patients for clinical trials, he says.

“We’re in a terrible situation with a very common, devastating disease. It’s devastating financially and it’s devastating emotionally to the families who have to cope with it, and we have nothing to give patients that will work,” Goldstein says.

Finding a treatment for disabling conditions like Alzheimer’s disease was one of the driving reasons for the passage of proposition 71, which created CIRM. Leeza Gibbons has served on our board as a patient advocate for Alzheimer’s disease and is one of the patient advocate board members who help keep the board’s focus on therapies and patients who need them. Her mother had Alzheimer’s disease. She went on to found Leeza's Place to support the caregivers of people with Alzheimer's disease and other conditions.

CIRM has funded $11 million in awards focusing on Alzheimer’s disease. You can see a list of those awards here.

CIRM did a video with Fred Gage, one of the co-authors on this paper, talking about the use of stem cells in modeling diseases:


A.A.

Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, & Goldstein LS (2012). Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature PMID: 22278060

Early results from two embryonic stem cell-based trials show promise

Yesterday, the company Advanced Cell Technology announced that two people in their clinical trials testing an embryonic stem cell-based therapy for forms of blindness is not only safe so far, but shows tentative early signs of restoring some vision in two patients. The work was published online January 23 in the journal The Lancet.

Of the two women discussed in the paper one had macular degeneration, the leading cause of blindness, and the other had the most common form of blindness in children, called Stargardt’s macular dystrophy. Both were participating in phase 1 trials testing cells derived from embryonic stem cells as a possible treatment for their blindness. All phase 1 trials are primarily designed to make sure a therapy is safe, but the researchers do also look for signs that the therapy might be effective. (We have more information about the phases of clinical trials on our website.)

The preliminary news that two women in these trials reported some improvements in vision warrants some cautious optimism. For those of us who have been following the field since the discovery of embryonic stem cells in 1998, this paper is a milestone. It’s the first published paper showing that—at least in this small number of patients for the first few months—the cells are safe.

However, two patients isn’t enough to show whether the therapy actually works. In fact, in a New York Times story Steven D. Schwartz, a professor of ophthalmalogy at UCLA's Jules Stein Eye Institute, who is leading the research, said there was evidence that at least one of the two patients might have experienced a placebo effect. Sorting out the real improvements from the placebos or short-term changes takes time, which is why clinical trials are set up to follow patients for several years. Only after many more people receive injections of the cells and are followed for several years will we know that the cells were effective.

A story by NPR quoted Schwartz:

Schwartz and his colleagues stressed that the findings are extremely preliminary and it's far too early to know anything for sure. The patients could continue to improve, or their vision could deteriorate again, he said. Many more patients will be needed to be treated for far longer to know whether the therapy is really safe and responsible for any improvement.

"My job is to decrease suffering, and if we overstate this and raise hopes falsely and then it doesn't work out, it will hurt people rather than help them," Schwartz said.

The Stanford University medical blog has more commentary on this trial from law professor Hank Greely. He's been following the field of embryonic stem cell research since the beginning and says the news is, "at least, a little exciting – and in a field that saw its first approved clinical trial stopped two months ago, even a little exciting news is very welcome." You can read more on their blog.

These are the only two trials currently underway testing an embryonic stem cell-based therapy. Along with the rest of the stem cell community we’ll be watching the results, and following the additional trials that are expected to start in the next few years. It’s through clinical trials such as these that safe and effective stem cell-based therapies will eventually reach patients.

A.A.

CIRM and Scotland team up in stem cell research collaboration

Last week CIRM and Scottish Development International, which promotes science research and economic development in Scotland, signed an agreement to collaborate on stem cell research.

This agreement marks 12th international funding agency to sign a collaborative agreement with CIRM. The agency also has agreements with federal and state funding agencies and foundations within in the U.S.

These agreements serve a valuable role in accelerating stem cell therapies. As a state agency, CIRM can only fund research within California. In some cases, however, those California scientists benefit from the expertise of colleagues who reside outside the state. With the collaborative agreements in place, the California scientists can find the best partners for developing new therapies. CIRM funds the California scientists and the collaborative funder supports the research in their jurisdiction.

We have a page on our website that lists the funding agreements and describes the process. You can also see all CIRM awards that include a collaborative funder. Altogether, these arrangements have leveraged more than $60 million dollars for stem cell research internationally.

The press release quotes Danny Cusick, president of the Americas for the Scottish Development International.

“We are committed to supporting Scottish-based companies to work with California scientists and businesses to further boost Scotland’s profile as the primary location to undertake clinical trials, create new opportunities for California companies to (invest) in Scotland and increase customers for our rapidly growing stem cell supply chain.”

CIRM president Alan Trounson talks about the collaborative funding agreements as creating a 24-hour-per-day stem cell workforce. “With our partners located around the world, the sun never sets on CIRM teams working toward new therapies.”

A.A.

Genomics initiative creates California infrastructure for speeding stem cell research

Earlier this week the CIRM governing board approved $40 million to fund a stem cell genomics initiative (here’s our press release). Stay with me here—this is actually really cool stuff, and crucial if we’re going to be able to generate the kinds of stem cell-based therapies patients and their families are waiting for.

Genomics is the study of all the DNA in a cell. That includes the actual sequence of the DNA, which is the same in all the cells of a person’s body, as well as the molecular decorations hanging on to the DNA. Those decorations, collectively called epigenetics, can determine the behavior of the genes such as which are active or inactive in a given cell. It’s epigenetics that can control why, if a hair cell and a liver cell have the same DNA, one makes hair and the other makes liver enzymes. Those epigenetic changes are also responsible for why an embryonic stem cell behaves one way, and the neuron it can mature into behaves differently.

Genomics also reveals molecules called RNA that are coded by the DNA and controlled by epigenetics. RNA can reveal a cell’s status as it differs from cell to cell depending on what kind of cell it is and whether the cell is healthy, diseased, or in damaged tissue.

Here are a few examples of how genomics is important for stem cell research. Let’s say a team wants to create reprogrammed iPS cells from the skin of a person with a genetic disease like Parkinson’s disease. First, those researchers need to know whether the process of reprogramming that skin cell into an embryonic-like cell altered the DNA. There’s a lot of controversy over whether iPS cells truly mimic embryonic stem cells (which we blogged about here), and knowing more about the genomics of iPS cells will help develop the best methods for creating those cells. This will also help the CIRM’s cell banking initiative, which will fund researchers to create and bank iPS cells in addition to banking embryonic stem cells for widespread distribution to stem cell researchers. With access to genomics resources we can be sure those iPS cells are genetically normal and consistent.

If we want to study and treat Parkinson’s disease, the next step would be to mature those iPS cells into dopaminergic neurons ,the type of neuron that goes awry in the disease. Genomic analysis will tell researchers whether the dopaminergic neurons are different when they are generated from skin cells of people without the disease and from people with the disease. Those differences could reveal a lot about what causes the disease in the first place. The information can also be used to screen for drugs that make neurons from people with the disease more like their normal, non-diseased counterparts.

The information is incredibly powerful. It’s also growing much, much cheaper. In the past it was too expensive and time-consuming to routinely carry out genomic analysis. With those costs coming down, and the process speeding up, it’s a good time to invest in genomics resources that would be available to California researchers.

In a paper published this month in Nature Biotechnology, CIRM president Alan Trounson with Natalie DeWitt and Michael Yaffe of the science office wrote:

For California to take a firm and lasting grip on leadership in stem-cell research—and, as stated in Proposition 71, “advance the biotech industry in California to world leadership as an economic engine for California's future”—its scientists must have access to these technologies and moreover create a coordinated international enterprise to maximize the reach and impact of stem cell genomics. Genomics is creating a sea change in biomedical research and medicine, and accordingly, the California Institute for Regenerative Medicine (CIRM; San Francisco) can create a process through which stem-cell research can participate and even provide leadership in a new era of medicine… With judicious expenditure of CIRM funds, it should be possible to use existing resources to rapidly and efficiently build an effective stem-cell genomics infrastructure that will be unique in the world, thus positioning California as a leader in this critical area of basic and translational research while genomic technologies build steam in the next five years.

The group also points out that although several research institutes in other states provide comprehensive genomics centers, none exist in California. That’s despite the fact that several of the major companies that make genomics tools are located in the state.

The requests for applications (RFA) for this initiative will be posted on this page of the CIRM website this spring. If you haven’t already signed up, here’s a link where you can sign up to get an email alert whenever CIRM posts a new RFA.

A.A.

Dewitt ND, Yaffe MP, & Trounson A (2012). Building stem-cell genomics in California and beyond. Nature biotechnology, 30 (1), 20-5 PMID: 22231086

National war on Alzheimer's disease brings hope to patients and caregivers

In Washington D.C. this week, researchers and patient advocates are giving feedback on what will become the nation’s war on Alzheimer’s disease, which aims to prevent and treat the disease by 2025.

The Department of Health and Human Services released a draft Framework for the National Plan to Address Alzheimer’s Disease on January 9. After receiving feedback, the final draft is expected late January or early February, according to a story in U.S.A. Today. That story goes on to quote Carol Blackwell, whose husband has the disease and whose family has experienced the financial burden of high medical costs and reduced income:

"My mother-in-law has been in a facility for 15 years," Carol Blackwell says. "In 2005, after her husband died … she'd used up all her money (for care), and Bob had to file for Medicaid for her. She's been living at the government's expense since then. We have to prevent those costs down the road."

There are 5 million people living in the U.S. with Alzheimer’s disease, and 15 million people estimated to be providing care for family members with the disease. The emotional and economic toll from the disease can be devastating. CIRM board member Leeza Gibbons cared for her own mother, then went on to write the award-winning book “Take Your Oxygen First” to help other caregivers care for themselves. She also started Leeza’s Place to provide support for caregivers. She writes:

Life doesn't always go as planned. The people we love get sick, they get diseases and we often feel helpless to do anything about it. When you are a husband or wife, son or daughter, brother, sister or friend who takes care of someone in your family or someone you love, chances are you need help too. That's where we come in...

Leeza Gibbons and other patient advocate board members keep CIRM’s eye on the end goal of accelerating new therapies. CIRM has funded eight projects with a focus on Alzheimer’s disease, worth a total of $11 million. This page describes the CIRM-funded projects and includes a list of grants and other resources describing stem cell-based approaches to treating the disease.

The U.S. draft framework came out during what is also Canada’s Alzheimer’s Disease Awareness Month. The Canadian Minister of Health Leona Aglukkaq posted a message about the month:

Alzheimer's disease, or related dementia, affects an estimated 500,000 Canadians, and statistics predict that this number will double within a generation. Fortunately, for every person living with Alzheimer's disease, there are also many family members and friends providing care and support.

A major national push to treat Alzheimer’s disease will help all those people with the disease and their family members avoid the associated heartache and economic loss.

This video discusses advances in a stem cell-based therapy for Alzheimer’s by a CIRM funded team at University of California, Irvine:



A.A.

Ataxia patients and family members learn about stem cell progress

I was scheduled to give a talk to the Northern California Ataxia Support Group Saturday, just 15 minutes before the Fortyniners were about to begin their first playoff game in years. A colleague picked me up at the local BART train station and we drove up to a mostly empty parking lot at the church where the meeting was supposed to take place. We wandered through the empty upper halls and as we approached a stairwell started to hear voices. Turned out the church has a second parking lot on the back side that opens to a lower level—key for the 30 some individuals gathered that day, many mobility challenged, who were gathered around two long tables.

For them the chance to get together to share information about their poorly understood mix of diseases and to hear about the promise of stem cells was more important than the football game some commentators were calling historic. Ataxia refers to an assortment of conditions, some inherited and some sporadic that all involve the nervous system with primary symptoms related to gait and mobility. They also have the commonality of being relatively poorly understood and ineffectively treated with current standards of care.

I did not come prepared to offer them news that we were close to clinical trials using stem cells to treat their diseases. We are not. But I was armed with news of two grants CIRM has funded that have already improved our understanding of a couple of ataxias and perhaps opened up the opportunity to find more effective traditional small molecule drugs. CIRM has funded two teams, one at UCLA and one at Scripps, that are both using cell samples form ataxia patients to create reprogrammed stem cells, called induced Pluripotent Stem Cells (iPSC), to create “disease-in-a-dish” models.

One team has already published a journal article on its model of Friedreich’s Ataxia (Cell Stem Cell, November 5, 2010), which offered a better explanation of the mutation involved in the disease, offering a point of departure for addressing the mutation. The other team is working on a form of ataxia that goes by the acronym A-T that is a particularly debilitating form that strikes children. It was known to be caused by a type of mutation called a “nonsense” coding error in the DNA. The team had previously developed several compounds that would allow the patient’s cellular machinery to read through the nonsense coding and go ahead and produce the protein that is missing in these kids. But there is no animal model of these diseases so there was no way to do the pre-clinical testing required to put the compounds in clinical trials in humans. Now they will have a model, cells from patients in a dish. So, there is hope one of those compounds can be shown to be worthy of a clinical trial.

This meeting was one of many that CIRM holds with patient advocacy groups in California as a way of ensuring that those groups who have the most at stake know about progress being made in developing therapies for the diseases that matter to them. These groups played a critical role in the creation of CIRM, and continue to have a loud voice in pushing CIRM to maintain our focus on new therapies. CIRM also keeps advocacy at the core of its mission through input from the 10 patient advocates who serve on our board. Our board member Jeff Sheehy wrote a blog entry on the importance of patient advocates in steering funding agencies like CIRM.

My audience and I had a good conversation about the long-term hope stem cell research provides. They seemed excited by this hope, but also exhibited a gentle patience, probably a brand of patience that can only be instilled by years of living with an intractable disease.

I got home in time to see the final few incredible minutes of the nail-biting football game and to hear our neighborhood explode with fire crackers and honking horns, but I did not regret one bit missing those first three quarters of play. That game ending was just the icing on a very satisfying cake.

DG

Ku S, Soragni E, Campau E, Thomas EA, Altun G, Laurent LC, Loring JF, Napierala M, & Gottesfeld JM (2010). Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability. Cell stem cell, 7 (5), 631-7 PMID: 21040903

Second synthetic trachea transplant shows promise of tissue engineering, regenerative medicine

Today brought the news of a second transplanted synthetic trachea seeded with a person’s own stem cells. As with the first such transplant, carried out last June, this one replaced the trachea in a person whose own windpipe had been damaged by cancer.

The timing on this story is exciting for us at CIRM. We’re currently hosting a group of tissue engineering experts—including Martin Birchall who was part of the team that carried out the first tissue engineered tracheal transplant—to help the agency understand how we could move the field forward. Other people at this workshop are working on projects to develop intestines, repair hearts, and generate synthetic polymers to help keep stem cells intact and alive during a transplant.

CIRM president Alan Trounson was quoted in the New York Times story about the transplant. He said that he was worried about the patient’s body responding to the foreign object and encapsulating it:

While he described Dr. Macchiarini’s work as “terrific,” he said he was not sure how long such a transplant could be expected to last.

“It looks very functional at this stage,” Dr. Trounson said. “But there’s going to be a reaction of some kind.” More work will probably be needed to develop scaffold materials that are optimized to reduce the response,” he added. This concern about preventing the body from rejecting engineered structures is one that has come up regularly among the experts CIRM is meeting with today. Another major topic of discussion is how to prove to the Food and Drug Administration that engineered structures are safe for use in humans.

In September CIRM held a webinar on scaffolding that included speakers from the FDA. One goal of that webinar was to help inform researchers about the regulatory process for developing stem cell therapies based on engineered scaffolding, such as the trachea. We’re hoping that through these webinars and by speaking with experts in the field, CIRM can help bring this promising area of research to more patients. That webinar and the associated slides are available on our website.

A.A.

CIRM boosts industry outreach efforts in 2011, more to come

Cynthia Schaffer is Contract Administrator and Compliance Officer at CIRM

As CIRM-funded teams move closer to clinical trials, we’re ramping up our engagement with the industry partners who are integral to the success of most future stem cell therapies. In my role supporting many of these endeavors I saw a significant uptick in 2011 in events and activities specifically focusing on these crucial industry groups.

For the second year in a row, CIRM organized webinars and roundtables with the FDA, industry and investigators from academia. These events focused on the challenges and/or roadblocks on the regulatory pathway to develop stem cell based therapies. Topics of these webinars included Imaging in May, Scaffolding in September and Immune Response in October.

Through our active engagement with the Alliance for Regenerative Medicine (ARM), CIRM sponsored the first ever regenerative medicine investor partnering event in November in conjunction with CONNECT and the Stem Cell Meeting on the Mesa. My colleague Elona Baum, CIRM General Counsel and Vice President of Business Development, was one of the primary organizers of this event, which was attended by more than 240 regenerative medicine professionals and featured 40 company presentations and a full day of panel discussions addressing key business topics. Participants came from across the regenerative medicine sector including big pharma, investors, leaders from Europe and Asia, therapeutic and platform companies, investigators and representatives from several prominent CIRM disease teams.

As part of the update to CIRM’s Strategic Plan, CIRM held four public meetings in October, two of which specifically targeted input from the for-profit sector of the Regenerative Medicine industry. The Strategic Plan update will be presented to the board at the upcoming governing board meeting January 17 in San Diego (location and audiocast details are available here).

At CIRM’s Grantee Meeting in September, 12 vendors from various for-profit companies who serve the regenerative medicine industry were able to exhibit their wares. This program was well received and we plan to incorporate this element again at our next CIRM Grantee Meeting in 2013.

In 2011 CIRM hosted two webinars on its new Disease Team Therapy RFA to help potential applicants understand CIRM’s expectations for their proposals and budgeting materials. These webinars append the 2010 Grant Writing webinar (archived on CIRM’s website) and similar curriculum is planned for 2012.

Also this year, CIRM allocated a significant $57 million to be invested in initiatives that will make the organization more flexible in seizing funding opportunities and partnering with industry (we blogged about those initiatives here). Baum said:

“We were very pleased with the Board’s approval in December of all three components of the Opportunity Fund: Bridge Funding ($12 million), External Innovation ($15 million) and the Strategic Partnership program ($30 million). We believe the Opportunity Fund and its components will give us increased flexibility in responding to opportunities that arise in the Regenerative Medicine industry.”

In addition to resources I link to here, I would specifically like to call your attention to the materials on Resources for Researchers page.

If you want to be alerted about upcoming industry events, you can sign up to receive notifications for all upcoming meetings here.

C.S.

CIRM-funded building at UC Irvine receives LEED Platinum certification

Michelle Kim / University Communications

In May 2010 University of California Irvine opened their new stem cell building funded in part by CIRM. In addition to its state-of-the art research facilities designed to speed the development of stem cell therapies, the Sue & Bill Gross Hall also recently received LEED Platinum certification from the U.S. Green Building Council.

According to a press release from UCI:

Gross Hall scored points for such features as dimmable and occupancy-controlled lighting, use of energy-saving building materials, and mechanical systems that are 50 percent more efficient than required by California’s Title 24 energy code. The operable windows are tied into the heating and air-conditioning controls so that when a window is opened, mechanical ventilation of that room shuts off.

An $80 million, 100,000-square-foot structure, Gross Hall was designed to facilitate contact between patients in the first-floor clinic and rehabilitation center and stem cell researchers on the first, second and third floors. Labs are equipped with Aircuity technology that monitors indoor air quality and adjusts air-change rates based on contaminant levels.

UCI received $27 million from CIRM for the building and a $10 million from Sue & Bill Gross. The remaining funds came from donations and institutional commitments leveraged by CIRM's investment. This is one of the 12 buildings supported through CIRM's Major Facilities programs. The complete list of those buildings is available here. The 12 major facilities received $272 million from CIRM, with private donations and institutional investments bringing the project totals to more than $1 billion. An independent review of the impact of this investment for the state economy suggested that the projects would create 13,000 job years of employment and $100 million in tax revenue.

A.A.

60 Minutes highlights concerns about clinics marketing unverified stem cell treatments

Last night, 60 minutes aired a report describing the dangers of what has become known as stem cell tourism – people traveling to other countries to receive unverified “treatments”. You can watch the episode here. In the story, they spoke with Gary Susser, whose son Adam has cerebral palsy. Susser and his wife took Adam to a doctor in Mexico, who injected Adam with stem cells but provided no evidence that the injections would be effective. They were not. In the story Susser said:

"I see how people are preyed upon by hucksters and charlatans. And people who have a special child don't need any more expense, don't need any more heartache, and don't need any more false promises. They need the truth and they need hope."

Susser and his wife worked with 60 minutes to investigate a clinic in Ecuador that advertises therapies for 70 incurable diseases including cerebral palsy.

This trend of overseas clinics offering “modern day miracles,” as the Ecuadorian clinic’s website promises, is one that has concerned both CIRM and the International Society for Stem Cell Research (ISSCR). In 2010, when the ISSCR held its annual meeting in San Francisco, CIRM and ISSCR co-hosted a symposium about these clinics and the concerns they raise. A video of that session is available on the CIRM website.

At that same meeting, then-head of the ISSCR Irv Weissman used his opening address to both tout a new ISSCR website designed to help people identify clinics offering true therapies (A Closer Look at Stem Cell Treatments), and also discussed what he saw as the dangers of stem cell tourism. In countries without strong oversight bodies such as the Food and Drug Administration in the U.S., clinics can make claims about potential therapies without backing those claims up with any proof that the procedure will work or even be safe. An investigational treatment offered for sale, which is what these clinics described on 60 minutes are offering, is not the same as a clinical trial, which would show whether the new treatments are safe and effective.

In the 60 minutes piece, the clinic under investigation had proposed injecting cells that, when scrutinized by Dr. Joanne Kurtzberg of Duke University, turned out to be disintegrating. She said:

"There are huge dangers if you injected that into someone's blood or spinal fluid because all these little fragments and debris would get trapped somewhere in the blood stream and could cause a stroke, or in the brain could cause an inflammatory reaction."

Weissman spoke with Stanford’s Krista Conger, who wrote a story on the topic for the magazine Stanford Medicine. In it Weissman said:

“This is a new field. We are learning what kinds of stem cells can regenerate which kinds of failing organs. But we always remember that our first goal is to do no harm. That’s why we begin our tests in animals before moving into early phase clinical trials in humans, and at every stage we verify the solidity and reproducibility of the science and that the investigators have no potential commercial or personal conflicts of interest that could influence the outcome of the trials. Any attempt to commercialize unproven treatments in the absence of independent or regulatory oversight endangers not only the lives of those who receive the treatments, but also the entire field of regenerative medicine.”

Conger also quoted CIRM grantee Jeanne Loring, director of the Center for Regenerative Medicine at the Scripps Research Institute in La Jolla, Calif.:

“When we report something good about stem cells, it gets picked up in the media, or in a blog that patients read. It gives them more ammunition to say that the FDA is stupid for denying access to treatments that seem like they should work.”

At CIRM, we know how frustrating the timeline of developing new therapies can be. We also have friends and family members with diseases desperately in need of new therapies. That sense of urgency is constantly reiterated by our board members, ten of whom serve on the board as patient advocates. (Our board member Jeff Sheehy has blogged about the role of advocates in accelerating the pace of new therapies.)

That’s why we’re working with industry, pushing teams to collaborate, and engaging the FDA to try to speed that timeline and get new therapies to the patients who need them. Today we have 43 projects in various stages of working their way to the clinic, with several we hope to see enter clinical trials in the next few years. You can read more about our projects in development and the steps along the path to a new therapy on our website.

If people are considering clinics outside the U.S., please do read the ISSCR web page. They have a good list of qualifications to look for in identifying clinics that are being truthful about what they offer rather than simply peddling hope. Included in what they suggest people look for is oversight of investigational treatments to be sure the physicians are qualified, the investigational treatment is prepared appropriately, and that the risks and potential benefits are accurately and clearly explained. People should also look for published records showing results from clinical trials. CIRM also has a page about stem cell tourism and what we are doing to try to speed the timeline to new therapies.

A.A.

CIRM's 1,000th published paper targets Huntington's disease

CIRM recently realized a noteworthy milestone with the publication of the 1,000th CIRM-funded paper in early December (here is a link to that paper). This is exciting to me personally because one of my first assignments when I joined CIRM three years ago was to develop (in collaboration with my Science Office colleague Rahul Thakar) a system and database for tracking CIRM-funded publications. At that point, there were only around 100 CIRM-funded papers, mostly from training grants, which were the first grants CIRM awarded in the spring of 2006. Watching the database grow and the publication rate accelerate has been exciting because these papers describe real progress that CIRM grantees are making in understanding stem cell biology, mechanisms of human disease and advancing stem cell-based therapies to the clinic.

The 1,000th paper itself is a great example of this progress. It was published in the journal Molecular & Cellular Neuroscience by Drs. Scott Olson, Jan Nolta and colleagues at UC Davis with the title “Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington's disease affected neuronal cells for reduction of huntingtin”. The fact that the thousandth journal article comes from Jan Nolta's lab has added significance given that she was just yesterday named editor of one of the leading specialty journals in the field Stem Cells.

The promising research described in this paper was funded in large part by a CIRM Early Translational grant to Nolta, which has the goal of developing a combination cell and gene therapy candidate to treat Huntington’s Disease, a devastating neurological disease for which there is no effective treatment. Among those who have suffered and died from Huntington’s is one of my favorite songwriters, Woody Guthrie, whose 100th birthday will be celebrated in July. There's more information about Huntington's disease and awards we've funded available on our website.

In Huntington’s Disease, a mutated form of a protein called huntingtin causes certain neurons in the brain to die. The goal of Nolta’s award is to use stem cells to disable the ability of those neurons to make the disease-causing protein. In their paper, Nolta and colleagues show that a type of stem cell found in the bone marrow called mesenchymal stem cells (MSCs) can be engineered to produce a molecule that inhibits the production of the mutated huntingtin protein. They show, in a petri dish, that this molecule is secreted by the stem cells, is taken up by nearby neuronal cells, and reduces the amount of the disease-causing protein produced by those cells. The next important step will be testing these engineered stem cells in an animal model of Huntington’s.

With over a thousand CIRM-funded publications come a lot of data and statistics that allow us to assess our programs and progress. Of the 1,009 CIRM-funded publications, 770 describe original research, 175 are literature reviews and 64 describe novel scientific methods. The top four RFAs by publication number are, not surprisingly, the four earliest in CIRM’s funding history: Training grants with 574 publications, New Faculty with 178, Comprehensive with 169 and SEED with 160. CIRM funding has resulted in an impressive number of papers in elite journals: 55 in Nature, 47 in Cell Stem Cell, 24 in Cell and 13 in Science. In total,298 CIRM-funded papers have been published in journals with impact factors greater than 10. There were 10 CIRM-funded publications in 2006, 68 in 2007, 151 in 2008, 224 in 2009, 261 in 2010, and 295 in 2011, so I predict that I’ll be back to blog about the 2,000th paper before the end of 2014!

Zachary Scheiner is a Science Officer at CIRM


Olson SD, Kambal A, Pollock K, Mitchell GM, Stewart H, Kalomoiris S, Cary W, Nacey C, Pepper K, & Nolta JA (2011). Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington's disease affected neuronal cells for reduction of huntingtin. Molecular and cellular neurosciences PMID: 22198539

Looking ahead to 2012

Yesterday CIRM president Alan Trounson took a look back over his science picks from 2011. Today, we're looking ahead to what's in store in 2012.

First, anyone interested in participating in the 2012 board meetings should take a look at the governing board meeting schedule. That's available here. We'll be having seven meetings at locations throughout California. As always, you can see any scheduled subcommittee or working group meetings on this page and you can also sign up to receive email notifications whenever we post new agendas. That sign up is here.

Those meetings will be action-packed in 2012, with $370 million in new awards slated for review by the governing board and a new strategic plan that will help guide the agency's priorities going forward. The awards scheduled for review this year include the next round of Creativity Awards worth $2.2 million, which fund high school students to carry out research in California stem cell labs. Last year's students who participated in our pilot program were outstanding, as you can see in this video:



The governing board will also be considering research awards that cover the complete therapy development pipeline (you can read more about that development pipeline on our website). The fourth round of Basic Biology awards, worth up to a total of $35 million, will continue CIRM's commitment to funding the basic discoveries that fuel new therapy ideas and also help resolve scientific issues that arise further down the pipeline.

The Early Translational III awards, worth up to a total of $95 million, will fund researchers who are in the early stages of translating a basic discovery into a future therapy. Some of our past recipients of Early Translational Awards have had such success that they are now applying for our second round of Disease Team Awards, worth up to $240 million. As with the past round of these awards, the disease teams include people with clinical, research and regulatory expertise who work together to bring their therapy candidate to clinical trials.

If you don't already receive CIRM press releases or monthly newsletters you can sign up here. They'll include information about awards we've funded and other decisions by the governing board.

A.A.

Guest blogger Alan Trounson — December’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s full report, along with an archive of past reports, is available on the CIRM website.

My review this month starts with a couple papers that further cement the high value of reprogrammed iPS cells as “disease-in-a-dish” models. This time they found the underlying mechanisms of the autism seen in Timothy Syndrome (blogged about here) and the bone and cartilage abnormalities seen in Marfan Syndrome.

But I want to take this space to note a different type of paper, one discussing a single patient, but a patient that would probably not be alive today without stem cells and a very creative international team of scientists. The team headed by a group at the Karolinska Institute in Sweden also had inputs from researchers in England, Germany and Iceland.

The patient had recurrent cancer in his trachea and little hope with traditional therapy, so the team built him a new airway. They first imaged his diseased trachea with a CT scan and then used that picture to build an artificial polymer scaffold of the same size and shape. They seeded this replica with stem cells from the patient’s own bone marrow and grew it in a bioreactor for 36 hours.

The new trachea was functional at the time of transplant, but the team gave the patient two growth factors to enhance the maturation of the airway. It seems like the patient’s own repair systems also kicked in because the team was able to detect other stem cells summoned to the site and other growth factors released by neighboring cells.

The patient is alive and cancer-free five months after the surgery. He is living “proof of concept” for an entire branch of regenerative medicine that seeks to build replacement tissues to order. We blogged about this advance here.

I began blogging about my science picks just a few months ago. You can read my 2011 science highlights in review in the following blog entries:

• November
• October
• September
• August
• July
• May
• April

A.T.