It’s appropriate that at the start of Women’s History Month, UC Davis’ Dr. Diana Farmer is making a little history of her own. She launched the world’s first clinical trial using stem cells to treat spina bifida before the child is born.
Spina bifida is a birth defect caused when a baby’s spinal cord fails to develop properly in the womb. In myelomeningocele, the most severe form of spina bifida, a portion of the spinal cord or nerves is exposed in a sac through an opening in the spine. Most people with myelomeningocele have changes in their brain structure, leg weakness, and bladder and bowel dysfunction.
While surgery can help, Dr. Farmer says it is far from perfect: “Currently, the standard of care for our patients is fetal surgery, which, while promising, still leaves more than half of children with spina bifida unable to walk independently. There is an extraordinary need for a treatment that prevents or lessens the severity of this devastating condition. Our team has spent more than a decade working up to this point of being able to test such a promising therapy.”
The team at UC Davis – in a CIRM-funded study – will use a stem cell “patch” that is placed over the exposed spinal cord, then surgically close the opening, hopefully allowing the stem cells to regenerate and protect the spinal cord.
In a news release Dr. Aijun Wang, a stem cell bioengineer, says the team has been preparing for this trial for years, helping show in animals that it is safe and effective. He is hopeful it will prove equally safe and effective in people: “Our cellular therapy approach, in combination with surgery, should encourage tissue regeneration and help patients avoid devastating impairments throughout their lives.”
Dr. Farmer says the condition, while rare, disproportionately affects Latinx babies and if the procedure works could have an enormous impact on their lives and the lives of their families: “A successful treatment for MMC would relieve the tremendous emotional and economic cost burden on families. We know it initially costs approximately $532,000 per child with spina bifida. But the costs are likely several million dollars more due to ongoing treatments, not to mention all the pain and suffering, specialized childcare, and lost time for unpaid caregivers such as parents.”
Here is video of two English bulldogs who had their spinal injuries repaired at UC Davis using stem cells. This was part of the research that led to the clinical trial led by Dr. Farmer and Dr. Wang.
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future.We kick off this event with a letter from our the Chair of our Board, Jonathan Thomas.
When voters approved Proposition 14 last November, they gave the Stem Cell Agency a new lease on life and a chance to finish the work we began with the approval of Proposition 71 in 2004. It’s a great honor and privilege. It’s also a great responsibility. But I think looking back at what we have achieved over the last 16 years shows we are well positioned to seize the moment and take CIRM and regenerative medicine to the next level and beyond.
When we started, we were told that if we managed to get one project into a clinical trial by the time our money ran out we would have done a good job. As of this moment we have 68 clinical trials that we have funded plus another 31 projects in clinical trials where we helped fund crucial early stage research. That inexorable march to therapies and cures will resume when we take up our first round of Clinical applications under Prop 14 in March.
But while clinical stage projects are the end game, where we see if therapies really work and are safe in people, there’s so much more that we have achieved since we were created. We have invested $900 million in basic research, creating a pipeline of the most promising stem cell research programs, as well as investing heavily on so-called “translational” projects, which move projects from basic science to where they’re ready to apply to the Food and Drug Administration (FDA) to begin clinical trials.
We have funded more than 1,000 projects, with each one giving us valuable information to help advance the science. Our funding has helped attract some of the best stem cell scientists in the world to California and, because we only fund research in California, it has persuaded many companies to either move here or open offices here to be eligible for our support. We have helped create the Alpha Stem Cell Clinics, a network of leading medical centers around the state that have the experience and expertise to deliver stem cell therapies to patients. All of those have made California a global center in the field.
That result is producing big benefits for the state. An independent Economic Impact Analysis reported that by the end of 2018 we had already helped generate an extra $10.7 billion in new sales revenue and taxes for California, hundreds of millions more in federal taxes and created more than 56,000 new jobs.
Used our support for stem cell research to leverage an additional $12 billion in private funding for the field.
Enrolled more than 2700 patients in CIRM funded clinical trials
In many ways our work is just beginning. We have laid the groundwork, helped enable an extraordinary community of researchers and dramatically accelerated the field. Now we want to get those therapies (and many more) over the finish line and get them approved by the FDA so they can become available to many more people around the state, the country and the world.
We also know that we have to make these therapies available to all people, regardless of their background and ability to pay. We have to ensure that underserved communities, who were often left out of research in the past, are an integral part of this work and are included in every aspect of that research, particularly clinical trials. That’s why we now require anyone applying to us for funding to commit to engaging with underserved communities and to have a written plan to show how they are going to do that.
Over the coming month, you will hear more about some of the remarkable things we have managed to achieve so far and get a better sense of what we hope to do in the future. We know there will be challenges ahead and that not everything we do or support will work. But we also know that with the team we have built at CIRM, the brilliant research community in California and the passion and drive of the patient advocate community we will live up to the responsibility the people of California placed in us when they approved Proposition 14.
We have all read about people who smoke a pack of cigarettes and drink a bottle of whiskey a day and somehow manage to live a long, healthy life. Then there are people like Sandra Dillon. She lived as healthy a life as you can imagine; she exercised a lot, ate a healthy diet and didn’t smoke. Yet at the age of 28 she was diagnosed with a rare and deadly form of blood cancer called myelofibrosis.
Sandra underwent the traditional forms of treatment but those proved ineffective and time seemed to be running out. Then she heard about a clinical trial for a new, experimental stem cell therapy, with Dr. Catriona Jamieson at the University of California San Diego.
Sandra says she wasn’t looking forward to it, but she was in a lot of pain, was getting much sicker and none of the treatments she tried was working.
“At the time I was actually quite afraid of seeing doctors or going to medical institutions. My experience had been rough, and I knew that I had to overcome my fear of going to hospitals and being treated. But it was a chance to have hope and to be on something that might work when there was nothing else available.”
Dr. Jamieson’s approach (CIRM helped support her early work in this area) had led to her identifying how abnormal gene activity was responsible for the progression of this form of blood cancer. With that knowledge she then identified a specific small molecule known to inhibit this mutant gene activity, and how it could halt the disease.
That’s what happened with Sandra. She says after years of pain and exhaustion, of fearing that she was running out of time, the treatment produced impressive results.
“It was pretty amazing. I had really low expectations from how sick I was and that this was experimental, and it was cancer and you expect it to be awful. And my experience was the opposite of what I’d expected. I started to feel incredible. The pain, after a few months, the side effects from my cancer started to come down.”
Today Sandra’s cancer is still in remission. She is back to her old, healthy, energetic self. She says she doesn’t consider herself a stem cell pioneer but is glad her participation in the trial might also benefit others.
“It’s helped me but the opportunity that it could also help other people is truly meaningful.”
The treatment she received was approved by the US Food and Drug Administration in 2019, the first approval for a therapy that had CIRM support.
I recently had the great pleasure of interviewing Sandra as part of our CIRM 2020 Grantee Meeting.
Funding models are rarely talked about in excited tones. It’s normally relegated to the dry tomes of academia. But in CIRM’s case, the funding model we have created is not just fundamental to our success in advancing regenerative medicine in California, it’s also proving to be a model that many other agencies are looking at to see if they can replicate it.
A recent article in the journal Cell & Gene Therapy Insights looks at what the CIRM model does and how it has achieved something rather extraordinary.
Full disclosure. I might be a tad biased here as the article was written by my boss, Dr. Maria Millan, and two of my colleagues, Dr. Sohel Talib and Dr. Shyam Patel.
I won’t go into huge detail here (you can get that by reading the article itself) But the article “highlights 3 elements of CIRM’s funding model that have enabled California academic researchers and companies to de-risk development of novel regenerative medicine therapies and attract biopharma industry support.”
Those three elements are:
1. Ensuring that funding mechanisms bridge the entire translational “Valley of Death”
2. Constantly optimizing funding models to meet the needs of a rapidly evolving industry
3. Championing the portfolio and proactively engaging potential industry partners
As an example of the first, they point to our Disease Team awards. These were four-year investments that gave researchers with promising projects the time, support and funds they needed to not only develop a therapy, but also move it out of academia into a company and into patients. Many of these projects had struggled to get outside investment until CIRM stepped forward. One example they offer is this one.
“CIRM Disease Team award funding also enabled Dr. Irving Weissman and the Stanford University team to discover, develop and obtain first-in-human clinical data for the innovative anti-CD47 antibody immunotherapy approach to cancer. The spin-out, Forty Seven, Inc., then leveraged CIRM funding as well as venture and public market financing to progress clinical development of the lead candidate until its acquisition by Gilead Sciences in April 2020 for $4.9B.”
But as the field evolved it became clear CIRM’s funding model had to evolve too, to better meet the needs of a rapidly advancing industry. So, in 2015 we changed the way we worked. For example, with clinical trial stage projects we reduced the average time from application to funding from 22 months to 120 days. In addition to that applications for new clinical stage projects were able to be submitted year-round instead of only once or twice a year as in the past.
We also created hard and fast milestones for all programs to reach. If they met their milestone funding continued. If they didn’t, funding stopped. And we required clinical trial stage projects, and those for earlier stage for-profit companies, to put up money of their own. We wanted to ensure they had “skin in the game” and were as committed to the success of their project as we were.
Finally, to champion the portfolio we created our Industry Alliance Program. It’s a kind of dating program for the researchers CIRM funds and companies looking to invest in promising projects. Industry partners get a chance to look at our portfolio and pick out projects they think are interesting. We then make the introductions and see if we can make a match.
And we have.
“To date, the IAP has also formally enrolled 8 partners with demonstrated commitment to cell and gene therapy development. The enrolled IAP partners represent companies both small and large, multi-national venture firms and innovative accelerators.
Over the past 18 months, the IAP program has enabled over 50 one-on-one partnership interactions across CIRM’s portfolio from discovery stage pluripotent stem cell therapies to clinical stage engineered HSC therapies.”
As the field continues to mature there are new problems emerging, such as the need to create greater manufacturing capacity to meet the growth in demand for high quality stem cell products. CIRM, like all other agencies, will also have to evolve and adapt to these new demands. But we feel with the model we have created, and the flexibility we have to pivot when needed, we are perfectly situated to do just that.
The Deseret News is Utah’s oldest continuously published daily newspaper. It has a big readership too, with the largest Sunday circulation in the state and the second largest daily circulation. That’s why when they publish paid advertisements that look like serious news articles it can be misleading, even worse.
This week the Deseret News (that’s not a misspelling by the way, the name is taken from the word for honeybee in the Book of Mormon) ran an advertisement written by the East West Health Clinic. The advertisement is about regenerative medicine and its ability to help repair damaged knee, hip and shoulder joints. It quotes from some well-regarded scientific sources such as WebMD and the National Health Interview Survey.
They also quote CIRM. Here’s what they say:
“In theory, there’s no limit to the types of diseases that could be treated with stem cell research,” the California Institute for Regenerative Medicine (CIRM) explains. CIRM posits that stem cell therapy could be used to “replace virtually any tissue or organ that is injured or diseased.”
That’s from a page on our website that talks about the potential of stem cell research. And it’s all true. But then the advertisement switches quickly, and rather subtly, to talking about what the clinic is doing. And that’s where things get murky.
East West Health offers therapies using umbilical and cord blood that they claim can treat a wide range of diseases and disorders from tendonitis to arthritis and suggest they might even help people with Alzheimer’s and dementia. But none of these have been proven in an FDA-sanctioned clinical trial or approved by the FDA. In fact, if you scroll down to the bottom of the website you find this statement.
*These statements have not been evaluated by the FDA*
And they also say that “Individual results may vary”.
I bet they do.
There are many clinics around the US that claim that stem cells have almost magical powers to heal. They don’t.
What stem cells do have is enormous potential. That’s why we invest in solid, scientifically rigorous research to try and harness that potential and bring it to patients in need. But that takes years of work, meticulous testing in the lab long before it ever is tried in people. It takes working with the FDA to get their support in starting a clinical trial to show that the therapy is both safe and effective.
CIRM has long promoted the importance of the Three R’s, making sure research is regulated, reliable and reputable. We want to help advance promising regenerative medicine therapies and products while protecting patients from the risks posed by unproven interventions.
That’s why we have a commitment to only funding the best science, work that has undergone rigorous peer review. That’s why we collaborate with expert advisors, ensure all projects we fund are in alignment with FDA rules and regulations and that meet the highest standards set by the organizations like the National Institutes of Health.
There are no short cuts. No easy ways to just stick cells in someone and tell them they are good to go.
That’s why when we see advertisements like the one that ran in The Deseret News it concerns us, because people will see our name and think we support the work being done by the people who wrote the piece. We don’t. Quite the opposite.
If you would like to learn more about the kinds of questions you need to ask before signing up for a clinical trial or therapy of any kind just go to our website. And if you want to see the list of clinical trials we do support, you can go here.
In response to the crisis caused by the COVID-19 virus in California and around the world the governing Board of the California Institute for Regenerative Medicine (CIRM) today held an emergency meeting to approve $5 million in rapid research funds targeting the virus.
“These are clearly extraordinary times and they require an extraordinary response from all of us,” says Dr. Maria T. Millan, President and CEO of CIRM. “Our mission is to accelerate stem cell treatments to patients with unmet medical needs. California researchers have made us aware that they are pursuing potential stem cell based approaches to the COVID-19 crisis and we felt it was our responsibility to respond by doing all we can to support this research and doing so as quickly as we possibly can.”
The Board’s decision enables CIRM to allocate $5 million in funding for peer-reviewed regenerative medicine and stem cell research that could quickly advance treatments for COVID-19. The funding will be awarded as part of an expedited approval process.
To qualify applicants would go through a full review by CIRM’s independent Grants Working Group.
Approved projects will be immediately forwarded to the CIRM Board for a vote
Projects approved by the Board would go through an accelerated contract process to ensure funds are distributed as quickly as possible
“Our hope is that we can go from application to funding within 30 to 40 days,” says Jonathan Thomas, PhD, JD, Chair of the CIRM Board. “This is a really tight timeframe, but we can’t afford to waste a moment. There is too much at stake. The coronavirus is creating an unprecedented threat to all of us and, as one of the leading players in regenerative medicine, we are committed to doing all we can to develop the tools and promote the research that will help us respond to that threat.”
Only projects that target the development or testing of a treatment for COVID-19 are eligible. They must also meet other requirements including being ready to start work within 30 days of approval and propose achieving a clear deliverable within six months. The proposed therapy must also involve a stem cell or a drug or antibody targeting stem cells.
The award amounts and duration of the award are as follows:
Award Amount and Duration Limits
Late stage preclinical
CIRM Board members were unanimous in their support for the program. Al Rowlett, the patient advocate for mental health, said: “Given the complexity of this situation and the fact that many of the individuals I represent aren’t able to advocate for themselves, I wholeheartedly support this.”
Dr. Os Steward, from UC Irvine agreed: “I think that this is a very important thing for CIRM to do for a huge number of reasons. The concept is great and CIRM is perfectly positioned to do this.”
“All hands are on deck world-wide in this fight against COVID-19.” says Dr. Millan. “CIRM will deploy its accelerated funding model to arm our stem cell researchers in this multi-pronged and global attack on the virus.”
Tomorrow, the last day in February, is Rare Disease Day. It’s a day dedicated to raising awareness about rare diseases and the impact they have on patients and their families.
But the truth is rare diseases are not so rare. There are around 7,000 diseases that affect fewer than 200,000 Americans at any given time. In fact, it’s estimated that around one in 20 people will live with a rare disease at some point in their lives. Many may die from it.
This blog is about one man’s work to find a cure for one of those rare diseases, and how that could lead to a therapy for something that affects many millions of people around the world.
Dr. Krystof Bankiewicz is a brain surgeon at U.C. San Francisco and The Ohio State University. He is also the President and CEO at Brain Neurotherapy Bio and a world expert in delivering gene and other therapies to the brain. More than 20 years ago, he began trying to develop a treatment for Parkinson’s disease by looking at a gene responsible for AADC enzyme production, which plays an important role in the brain and central nervous system. AADC is critical for the formation of serotonin and dopamine, chemicals that transmit signals between nerve cells, the latter of which plays a role in the development of Parkinson’s disease.
While studying the AADC enzyme, Dr. Bankiewicz learned of an extremely rare disorder where children lack the AADC enzyme that is critical for their development. This condition significantly inhibits communication between the brain and the rest of the body, leading to extremely limited mobility, muscle spasms, and problems with overall bodily functions. As a result of this, AADC deficient children require lifelong care, and particularly severe cases can lead to death in the first ten years of life.
“These children can’t speak. They have no muscle control, so they can’t do fundamental things such as walking, supporting their neck or lifting their arms,” says Dr. Bankiewicz. “They have involuntary movements, experience tremendously painful spasms almost like epileptic seizures. They can’t feed themselves and have to be fed through a tube in their stomach.”
So, Dr. Bankiewicz, building on his understanding of the gene that encodes AADC, developed an experimental approach to deliver a normal copy, injected directly into the midbrain, the area responsible for dopamine production. The DDC gene was inserted into a virus that acted as a kind of transport, carrying the gene into neurons, the brain cells affected by the condition. It was hoped that once inside, the gene would allow the body to produce the AADC enzyme and, in turn, enable it to produce its own dopamine .
And that’s exactly what happened.
“It’s unbelievable. In the first treated patients their motor system is dramatically improved, they are able to better control their movements, they can eat, they can sleep well. These are tremendous benefits. We have been following these children for almost three years post-treatment, and the progression we see doesn’t stop, it keeps going and we see these children keep on improving. Now they are able to get physical therapy to help them. Some are even able to go to school.”
For Dr. Bankiewicz this has been decades in the making, but that only makes it all the more gratifying: “This doesn’t happen very often in your lifetime, to be able to use all your professional experience and education to help people and see the impact it has on people’s lives.”
So far he has treated 20 patients from the US, UK and all over the world.
But he is far from finished.
Already the therapy has been given Orphan Drug Designation and Regenerative Medicine Advanced Therapy designation by the US Food and Drug Administration. The former is a kind of financial incentive to companies to develop drugs for rare diseases. The latter gives therapies that are proving to be both safe and effective, an accelerated path to approval for wider use. Dr. Bankiewicz hopes that will help them raise the funds needed to treat children with this rare condition. “We want to make this affordable for families. We are not in this to make a profit; we want to get foundations and maybe even pharmaceutical companies to help us treat the kids, so they don’t have to cover the full costs themselves.”
CIRM has not funded any of this work, but the data and results from this research were important factors in our Board awarding Dr. Bankiewicz more than $5.5 million to begin a clinical trial for Parkinson’s disease. Dr. Bankiewicz is using a similar approach in that work to the one he has shown can help children with AADC deficiency.
While AADC deficiency may only affect a few hundred children worldwide, it’s estimated that Parkinson’s affects more than ten million people; one million of those in the US alone. Developing this gene therapy technique in a rare disease, therefore, may ultimately benefit large populations of patients.
So, on this Rare Disease Day, we celebrate Dr. Bankiewicz and others whose compassion and commitment to finding treatments to help those battling rare conditions are helping change the world, one patient at a time.
It’s always gratifying when one of the projects you have funded starts to show promising results. It says your faith in the research and the researcher were well founded. But it’s also fun when the project you fund turns up some really cool findings and is picked as a top science story of the year.
That’s what happened with UC San Diego researcher Alysson Muotri’s work on growing brain organoids (tiny clumps of brain cells, created in a dish, that can mimic some of the properties of a real brain). His work, funded by yours truly, was chosen by Discover Magazine as one of the Top Ten Science stories of 2019.
When you read about a new drug or therapy being approved to help patients it always seems so simple. Researchers come up with a brilliant idea, test it to make sure it is safe and works, and then get approval from the US Food and Drug Administration (FDA) to sell it to people who need it.
But it’s not always that simple, or straight forward. Sometimes it can take years, with several detours along the way, before the therapy finds its way to patients.
That’s the case with a blood cancer drug called fedratinib (we blogged about it here) and the relentless efforts by U.C. San Diego researcher Dr. Catriona Jamieson to help make it available to patients. CIRM funded the critical early stage research to help show this approach could help save lives. But it took many more years, and several setbacks, before Dr. Jamieson finally succeeded in getting approval from the FDA.
The story behind that therapy, and Dr. Jamieson’s fight, is told in the San Diego Union Tribune. Reporter Brad Fikes has been following the therapy for years and in the story he explains why he found it so fascinating, and why this was a therapy that almost didn’t make it.
Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. It causes them to increase in number, crowd out other blood cells, leading to anemia, infection or heavy bleeding. Up until the early 2000’s the main weapon against CML was chemotherapy, but the introduction of drugs called tyrosine kinase inhibitors changed that, dramatically improving long term survival rates.
However, these medications are not a
cure and do not completely eradicate the leukemia stem cells that can fuel the
growth of the cancer, so if people stop taking the medication the cancer can
But now Dr. John Chute and a team of researchers at UCLA, in a CIRM-supported study, have found a way to target those leukemia stem cells and possibly eliminate them altogether.
The team knew that mice that had the genetic mutation
responsible for around 95 percent of CML cases normally developed the disease
and died with a few months. However, mice that had the CML gene but lacked
another gene, one that produced a protein called pleiotrophin, had normal white
blood cells and lived almost twice as long. Clearly there was something about
pleiotrophin that played a key role in the growth of CML.
They tested this by transplanting blood stem cells from mice
with the CML gene into healthy mice. The previously healthy mice developed
leukemia and died. But when they did the same thing from mice that had the CML
gene but lacked the pleiotrophin gene, the mice remained healthy.
So, Chute and his team wanted to know if the same thing
happens in human cells. Studying human CML stem cells they found these had not
just 100 times more pleiotrophin than ordinary cells, they were also producing
their own pleiotrophin.
In a news release Chute, said this was unexpected:
“This provides an example of cancer stem cells
that are perpetuating their own disease growth by hijacking a protein that
normally supports the growth of the healthy blood system.”
Next Chute and the team developed an antibody that blocked
the action of pleiotrophin and when they tested it in human cells the CML stem
Then they combined this antibody with a drug called imatinib
(better known by its brand name, Gleevec) which targets the genetic abnormality
that causes most forms of CML. They tested this in mice who had been
transplanted with human CML stem cells and the cells died.
“Our results suggest that it may be possible to eradicate
CML stem cells by combining this new targeted therapy with a tyrosine kinase
inhibitor,” said Chute. “This could lead to a day down the road when people
with CML may not need to take a tyrosine kinase inhibitor for the rest of their
The next step is for the researchers to modify the antibody so that it is better suited for humans and not mice and to see if it is effective not just in cells in the laboratory, but in people.