Helping grantees overcome barriers in the path to new therapies

We’ve been rolling out our 2011 Annual Report stories throughout the past few weeks. The full report is posted online and is available for download from our website. Today we are introducing a story about CIRM’s efforts to overcome barriers in the path to the clinic.

CIRM’s primary focus is on funding stem cell research. But in order for that research to benefit patients we also need to help our grantees overcome the many barriers that exist in getting their research into clinical trials and to people who are waiting for new therapies.

CIRM has ramped up efforts in the past year to connect grantees with the critical skills and information they need to succeed. That includes hosting webinars and partnering events with industry (those webinars are archived on our website). We also blogged about many of those activities back in January.

In the annual report story we write:

Duane Roth, who is co-vice chair of CIRM’s governing board, said that the three Rs of therapy development—Research, Regulatory pathway, and Reimbursement—are all barriers for stem cell therapies to overcome in the established path to the market. Roth is Chief Executive Officer of CONNECT, a non-profit organization that fosters entrepreneurship in the San Diego area.

“There are so many things in the research phase that are ill defined, and the regulatory process is ill defined,” Roth said. “The numbers don’t add up. How does the company get paid to earn a profit?”

Roth has also been promoting the role of patient advocates in regulatory decision-making. We write:

Roth acknowledges that getting scientists and industry talking is a good first step to speeding therapies, but thinks there’s one group missing: patient advocates.

Serving on CIRM’s governing board with ten patient advocates changed Roth’s perception about the role of the advocate in promoting new therapies. “They have an incredible ability to focus on the benefit because it’s personal,” he said.

You can read more about CIRM’s efforts to ensure research doesn’t falter on the path to clinical trials in the story online. This is the eighth annual report story we’ve posted. Here are the others:

You can also view the entire annual report on our website.

A.A.

How brain stem cells grow up: insights could aid in autism, brain tumors, language disorders

“Can one feel too attached? Does one need to let go to mature? Neural stem cells have this problem, too. “

So asks a UCLA press release about work by CIRM grantee Bennett Novitch. He and a team have been working to understand how neural stem cells understand when it’s time to leave their protected homes and migrate out to where they are needed in the brain. Their findings are critical for understanding some birth defects and also some nervous system diseases such as autism.

The press release describes when the stem cells multiply during development of the brain:

“During the first trimester of development, the neural stem and progenitor cells form a niche, or safe zone, within the nervous system. The neural stem and precursor cells adhere to each other in a way that allows them to expand their numbers and keep from differentiating.”

In a paper published today in Neuron, the team describes two genes that are essential for breaking the stem cells free of the niche and allowing them to migrate out into the brain and become neurons. The release quotes Novitch:

“We were also surprised to see how small changes in the degree of cell adhesion can markedly alter the development and structure of the nervous system. It’s all about balance, if you have too many or too few stem and precursor cells, the result could be disastrous.”

Novitch and his group hope to learn whether the same genes are also required for normal stem cell function in adult brains and in the growth of brain tumors. There are some hints that their results could also apply to some speech and language disorders and also autism.

You can read more about CIRM’s funding of autism research on our website. We also wrote about autism research by CIRM grantees in our annual report.

CIRM Funding: Bennett Novitch (RB1-01367)

A.A.

Sen. Art Torres discusses National Minority Health Month

Senator Art Torres (ret.) is CIRM’s statutory vice-chair

April has been designated as National Minority Health Month, a cause that is dear to my heart and an issue we take seriously at CIRM. That’s one of the reasons we created the Bridges to Stem Cell Research program, to create a pipeline program for students that would increase racial and ethnic diversity in the public health and biomedical sciences.

I was elected to the California Legislature in 1974, at the age of 28, arguing for better health care for my East Los Angeles District. In 1978, I assumed the Chairmanship of the Assembly Health Committee and introduced legislation to help create a single payer plan for California. It is now 2012 and we are still arguing about accessible health care for all Californians and the disparities which I debated in 1974 still exist today!

Differences in health outcomes have always been linked to health disparities within social, economic and environmental groups. When I worked with Cesar Chavez and the United Farm Workers to improve conditions for migrant farmers in the 1970s, pesticide poisonings were routinely dismissed as “flu symptoms”. It was only when trained physicians linked those symptoms to the use of toxic pesticides that tighter oversight of spraying was called for.

We know that race and ethnicity, or other characteristics such as gender or sexual orientation that have historically been linked to discrimination can influence health status.

A 2002 report by the Institute of Medicine -”Unequal Treatment Confronting Racial and Ethnic Disparities in Health Care” – concluded that it was the lack of insurance which propelled health care inequities, more than demographic or economic barriers. The study also stated that racial and ethnic minorities are significantly less likely than the rest of the population to have health insurance. According to the report these minorities make up around 30 percent of the US population yet make up more than 50 percent of the uninsured. Primary care physicians are also lacking in racial and ethnic communities where these children are less likely than non-Hispanic white children to have access to a primary doctor.

In addition the report found that African American children have higher hospitalization rates from influenza and are twice as likely to be hospitalized and more than four times as likely to die from asthma as non-Hispanic white children. The health care work force is also limited in its representation of people of color in their ranks. This also leads to disparities.

We know that the Affordable Care Act will provide insurance coverage to more than 30 million people but now that is facing an uncertain future. My dear friend Secretary Kathleen Sebelius, former Governor of Kansas, has developed an action plan “A nation free of disparities in health and health care” to be implemented through goals.

  1. Transform health care by reducing disparities in health insurance coverage and access to care.
  2. Strengthen the nation’s health and human infrastructure and workforce by identifying racial and ethnic health disparities so that these individuals can communicate properly with their health care providers. Utilize Promotoras, who provide health education and support to their communities. Start programs to increase diversity in health care and science.
  3. Advance health and safety by increasing availability of community-based programs through outreach and education.
  4. Advance scientific knowledge and innovation by increasing the availability and quality of data collected and reported on racial and ethnic minority populations by implementing a multifaceted health disparities data collection strategy across the agency.
  5. Increase efficiency, transparency and accountability of HHS programs through streamlining grant administration for health disparities funding.

In the 38 years since I was elected to office determined to improve access to health care we have made some progress, but not nearly enough. Hopefully National Minority Health Month will refocus our attention on the disparities we still have in America, and remind us that we still have much work to do.

I also hope that the diverse students receiving stem cell research training through the Bridges program will help bring a greater focus on minority health issues to the research community. These outstanding students will be a key part of fulfilling those five goals that will help bring us closer to becoming a nation free of health disparities.


CIRM Bridges: Training the Next Generation of Stem Cell Scientists 

Stem cells used to mimic heart condition in a lab dish, test therapies

There’s more news on heart disease today, this time from CIRM grantees at Stanford University. A team led by Joseph Wu used stem cells to create a model of a genetic disease called dilated cardiomyopathy in a lab dish and used that model to validate two approaches to treating the disease. Their work was published April 18 in the journal Science Translational Medicine.
The Stanford team collected skin cells from four people in a family that has an inherited form of dilated cardiomyopathy: a grandmother, two of her sons and a grandson. The fourteen year old grandson has such a severe form of the disease that he had already required a transplant. They then converted those cells to an embryonic-like state, called an iPS cell, and coaxed the cells to mature into heart tissue.

A Stanford press release describes their findings:

Wu and Sun also saw that the diseased cells exhibit structural differences and are more susceptible to mechanical stress than unaffected cells.
When the researchers treated the diseased cells with metoprolol, a beta blocker commonly used to treat cardiomyopathy, they found that it decreased the frequency of contractions as expected. It also increased the responsiveness of the cells to calcium and, over time, helped resolve some of the structural differences between affected and unaffected cells. What’s more, the team tried a gene therapy approach that is currently in clinical trials and found that it also improved the forcefulness of the cells’ contractions.

In addition to providing a way of understanding and finding therapies for this disease, the researchers say their approach could help test drugs for toxicity.
According to the Stanford release:

The implications of such research are huge. According to Wu, one of the major reasons cardiac drugs are pulled from the market is unexpected cardiac toxicity — that is, they are damaging the very hearts they’re meant to help. Currently, such drugs are pre-screened for toxic effects on common laboratory cell lines derived from either hamster ovaries or human embryonic kidney cells. Even though these ovarian and kidney cells have been artificially induced to mimic the electrophysiology of human heart cells, they are still very different from the real thing. A reliable source of diseased and normal human heart cells on which to test the drugs’ effect prior to clinical use could improve drug screening, save billions of dollars and improve the lives of countless patients.

This issue of testing drugs for possible side effects is one other CIRM grantees are also working on. We produced a video a few years ago with Bruce Conklin of the Gladstone Institutes talking about this approach.

CIRM Funding: Joseph Wu (RB3-05129)

A.A.

New CIRM initiative helps move promising therapies into clinical trials

Our ultimate goal at CIRM, from day one, has been to get therapies to the people who need them most, the patients. That’s why our energy is focused on working with scientists in the lab and clinic, and patient advocates to move the most promising research along the development pipeline as fast as possible. This week we unveiled an important new part of that process, our Strategic Partnership Award initiative. (You can read our press release about the news here.)

This new initiative by CIRM represents a $30 million commitment to try and attract industry engagement and investment in CIRM-funded stem cell research. It’s one part of a three-part initiative called the Opportunity Funds, which we blogged about when the governing board approved the programs in December.

As CIRM President Alan Trounson says in a news release:

“This initiative is a major new development in the progress towards providing new medical treatments for patients by engaging the most effective global industry partners.”

The hope is that the initiative, by making three or more awards of up to $10 million each, will help create partnerships between researchers and industry to move promising stem cell therapies into early stage clinical trials in patients.

Ingrid Caras, a Science Office at CIRM who played a major role in helping create the initiative, says the announcement reflects the progress that is being made in stem cell research:

“We believe that there are a number of promising candidate stem cell therapies in the research pipeline that are ready for clinical trials. However, trials can be expensive. This Strategic Partnership Awards initiative helps smooth out the path to clinical trials by spreading the cost between CIRM and pharmaceutical or biotech companies.”

K.M.

Scar tissue transformed into beating cells in the hearts of mice

Heart muscle cells directly reprogrammed from skin, Deepak Srivastava, Gladstone Institutes

CIRM grantees at the Gladstone Institutes in San Francisco have carried out a remarkable feat: They directly converted scar-forming cells in the mouse heart into beating cells.

We’ve previously blogged about work led by Deepak Srivastava, who had converted non-beating heart cells in the lab dish into beating cells. (These non-beating cells are called heart fibroblasts, which make up about half the cells of the heart.) In a press release that accompanied that 2010 publication, Srivastava had speculated that if the same feat could be carried out in the living heart it could represent a way of repairing damage after a heart attack.

Now, he and his team have shown that the same group of molecules that directed the cellular transformation in the lab dish is also effective in living heart tissue, at least in mice. The work appears today in the advanced online publication of Nature.

A press release from the Gladstone Institutes quotes Srivastava, who directs cardiovascular and stem cell research at Gladstone and was senior author on the study. Srivastava is also a professor at the University of California, San Francisco.

“The damage from a heart attack is typically permanent because heart-muscle cells—deprived of oxygen during the attack—die and scar tissue forms. But our experiments in mice are a proof of concept that we can reprogram non-beating cells directly into fully functional, beating heart cells—offering an innovative and less invasive way to restore heart function after a heart attack.”

This work builds directly on a discovery by another Gladstone scientist, Shinya Yamanaka, who in 2006 first showed that adult cells could be reprogrammed to an embryonic-like state. In recent years, researchers have expanded that work to convert adult cells directly into other types of adult cells. This is the first time the technique has been shown to work in a living animal.

As always, it’s important to note that there’s a big difference between mice and humans. Srivastava says the team’s next step is to see if their technique works in other animals before beginning work toward clinical trials in humans. If the work continues to go well, he says:

“We hope that our research will lay the foundation for initiating cardiac repair soon after a heart attack—perhaps even when the patient arrives in the emergency room.”

A.A.

CIRM funding: Li Quan (TG2-01160), Deepak Srivastava (RB3-05174)

Different voices at public hearing help CIRM focus on the future

It’s never easy to hear people criticize you in public, particularly when you think some of the criticism is misguided or just downright wrong. But while it’s never fun to hear those kinds of comments, it can be very instructive and even enlightening to see how others see you.

On Tuesday, April 10 the Institute of Medicine (IOM) held a public meeting at Irvine in Southern California to hear from a variety of people who have perspectives on CIRM, some good, some not so good.
(webcast audio recordings of the meeting are now available: Morning Session | Afternoon Session: part 1, part 2, part 3, part 4)

The hearing was part of the independent assessment that CIRM asked the IOM to carry out to look into our programs, operations, strategies and performance since its creation in 2005. Previous hearings have featured people who had positive things to say about the agency. The first half of this latest hearing was a little less easy on the ear with several people expressing their concerns about the agency, but it was clearly important for the members of the IOM to hear those opinions.

Changing for the better

What was most interesting, and encouraging, was that even those who were most critical of CIRM admitted that things were clearly changing for the better, that over the past year the agency was working in a more open and transparent way and responding to some of the criticisms of its early years.

We can all learn from our experience and do a better job as a result of them. CIRM is doing that and clearly we still have work to do. Hearing from our critics helps us understand how some others see us and what kinds of misperceptions are out there. Knowing what people are saying helps push us to do a better job of communicating, explaining what we are doing and why.

Focused on the future

But the IOM hearing was far from being all negative. The afternoon session featured four researchers who are using CIRM-funding to help drive their work. It was an exciting and enlightening presentation, a reminder of what we are really here to do, and of the progress that is being made and the benefits that patients and the people of California are already seeing.

K.M.

Progress Toward Therapies: CIRM’s therapies in development

Kevin McCormack is the new Sr. Director of Public Communications and Patient Advocate Outreach at CIRM. His first post on our blog introduces CIRM’s 2011 Annual Report section on our progress toward therapies. We’ve been rolling out annual report stories throughout the past few weeks and will be posting the full report online in early April.

Back in 2004 when Proposition 71 – creating the stem cell agency – was on the state ballot, I was working as a producer in local TV news in San Francisco. I did many stories on the issue and always came away thinking ‘what a cool idea that is.’ Fast forward to today and I’m the new kid on the block in the Communications department at CIRM and can’t quite get over the thrill of being here, being part of such an incredible group of people, and such incredibly important work.

After the initial flurry of stories about CIRM in 2004 the topic of stem cells dropped out of the news for a while. That’s understandable when you consider how back then the science of stem cells was still very much in its early days and that it takes time to produce results of any kind – even in the most basic of studies.

Today, I think a lot of people will be surprised to see just how far we have come in such a relatively short space of time. Since our founding CIRM has funded a couple of hundred grants that have laid the foundation of our understanding of stem cell science. By 2011 43 of those projects – in 26 different diseases – were in the transition to the clinic. Those covered a wide range of conditions from heart disease and leukemia, to Alzheimer’s and diabetes. Some of those studies are still in the early stages, establishing what’s called “proof of concept” to show that the theory behind the therapy works. Others are much further along the pipeline and much closer to clinical trials where those therapies will be tested in people.

Here’s a diagram that shows at a glance how many different kinds of studies we are doing and where they are on the development pipeline.

If you would like to see a more detailed breakdown of which specific diseases are being studied and the process of getting from basic science to therapies you can find that on our website section called Progress Toward Therapies.

Of course in many ways this is still just the beginning of our journey and our grantees still have a huge amount of work to do. But each month brings new findings from researchers around California, and indeed the world, of the power and potential of stem cell therapies. Many of those studies were funded by CIRM, or are the product of collaborations with CIRM-funded researchers. Each one adds another piece of knowledge to the field, helping take us ever closer to finding more effective treatments for deadly diseases.

In the coming months and years I will be sharing news of those developments with you, keeping you informed on progress in the research, and letting you know how our tax dollars are pushing forward the boundaries of science and making California the center of a whole new kind of research.

Here are links to stories from our 2011 Annual Report that we’ve introduced in previous blog entries:

Kevin McCormack Sr. Director of Public Communications and Patient Advocate Outreach kmccormack@cirm.ca.gov

UC Davis clinical trial helps bones heal

For Diana Souza, working on her 23-acre ranch in the mountains east of Redding, California is a labor of love. But last year, a fall from a ladder left her with a badly fractured left arm that would not heal. Her arm became deformed from the cumulative effects of that fall and two previous fractures and several surgeries and Souza was faced with the real possibility of having only one working arm.

Souza told the story of the clinical trial at UC Davis that returned strength to her arm at the CIRM governing board’s Spotlight on Disease seminar on March 21st in Sacramento. Videos from these talks are now available on our website. She attributed her positive outcome to her orthopedic surgeon, Dr. Mark Lee, an associate professor of surgery at the UC Davis School of Medicine, who led the clinical trial. He’s testing a way of using stem cells from a patient’s bone marrow to help heal difficult fractures:

It was his clinical research using stem cells that I think made the biggest difference in my case. I still had to undergo a lengthy surgery and somewhat painful recovery but he could not have accomplished nearly as much and help enable my weak and unhealthy bones to repair themselves without using the stem cells he extracted from my bone marrow to fill in the holes and gaps in my bone which strengthen the bone and finally allowed my arm to heal properly and look normal.

Souza’s story of a hard-to-heal fracture isn’t an isolated incident. Everyday Dr. Lee sees victims of high-energy trauma such as car accidents. In these cases, severe bone fractures can lead to such massive bone loss that realigning and fixing the bone with metal implants is not enough to heal the bone. Dr. Lee, who also spoke at the Spotlight, explained the problem further as he showed images of severe fractures:

What you can see here is a massive area of missing bone. I think it’s important to realize that this is an area that will not heal without help. It’s a problem we don’t have great solutions for at this point in time.

The current gold standard treatment for these fractures involves taking healthy bone from one part of the body and implanting it at the fracture site. Although the method can be effective it has many drawbacks including the limited amount of bone graft, a slow healing time and an overall low reliability. In the clinical trial that healed Souza’s arm, Lee isolated mesenchymal stem cells from her bone marrow and transplanted them into the site of her fracture. These cells have the ability to transform into osteoblasts, the bone-forming cells of the body. They also release proteins that help support bone repair and formation.

While Lee continues to optimize methods for harvesting mesenchymal stem cells, his colleague, Dr. Kent Leach, a biomedical engineer at the UC Davis College of Engineering, who also spoke at the meeting, is using these cells to discover better ways of growing new bone. He designs scaffolds that would ultimately be transplanted along with the stem cells to provide a temporary structure during the bone healing process. During the Spotlight seminar, Leach said that tweaking the composition of these scaffolds can significantly increase the ability of the stem cells to nurture the growth of new bone.

The hope at UC Davis is that these collaborative efforts between clinical researchers and biomedical engineers, not to mention veterinary researchers, will accelerate the path to new stem cell therapies. In her introduction to the talks, Claire Pomeroy, a CIRM governing board member and vice chancellor of UC Davis human health sciences, pointed out that this collaboration would not have been possible without CIRM support.

I would like to emphasize that all of these researchers work with the team at the UC Davis Good Manufacturing Practice facility located in the CIRM-supported Institute for Regenerative Cures [watch our video about that facility here]. That’s where these cells are being prepared in the safest and most efficient manner. With this collaboration and with support from CIRM, UC Davis is uniquely positioned, I believe, to move regenerative medicine from the basic science of biomedical engineering through small and large animal models at our veterinary school to human clinical trials at our medical center.

Diana Souza certainly can attest to some early success of these researchers’ efforts:

I’m healing. I’m healing quite well. My friends cannot believe the difference in my physical strength and well-being. And I cannot believe the difference. It’s incredible.

T.D.

James Till on the history and future of stem cells

Last week the Canadian magazine Macleans ran a Q&A with James Till, who, along with Ernest McCulloch, discovered stem cells almost 50 years ago. Together they won the prestigious Lasker Award in 2005 for their discovery, which was initially published in a 1963 Nature paper.

The pair identified the stem cells in bone marrow that produce all the cells of the blood – immune cells, red blood cells and platelets. These are the cells that rebuild the blood system in people who get a bone marrow transplant. They are also the basis for many CIRM-funded awards, including disease teams working toward therapies for HIV/AIDS and sickle cell disease. Ernest McCulloch died in early 2011.

In one question, MacLeans asked Till whether he had any idea what the cells would do for medical research. He replied:

For us, the potential for bone marrow transplantation was obvious. The potential for what is now called regenerative medicine wasn’t. It didn’t take off until 1998 when Thompson and Wisconsin showed that embryonic stem cells could be propagated in a cell culture. Then you can multiply these formerly rare cells by growing them in a culture. That raised the possibility that embryonic stem cells could be used for the kinds of things that are contemplated by those interested in regenerative medicine.

He went on to discuss cancer stem cell research in Canada, and mentioned the two Canadian scientists who are collaborative partners on CIRM disease team awards. (You can see summaries of those awards here.)

Toronto stem cell researchers John Dick and Tak Mak head up groups that have won funding in a competition set up by the California Institute of Regenerative Medicine to take the cancer stem-cell field to the point where a drug can be developed and be ready for regulatory approval. My belief is that they are both capable of doing it.

I particularly liked Till’s response to a request to speculate on the next 50 years of medical research. He told readers to expect the unexpected:

I believe stem cell research will continue to achieve unexpected things and that’s the only prediction I’m willing to make. It will be unexpected because that’s how science functions. And I don’t know when either. I would certainly have not predicted iPS cells, I would have thought that experiment wouldn’t work. It did!

Till has retired from research, but has still been active in the research community advocating for open access to medical journals. Most journals where scientists publish their results are only accessible to those with subscriptions. He says those results should be available to everybody, not just those in the ivory tower. CIRM is working to amend our regulations to require papers published with CIRM funding to be publicly available within one year.

A.A.