CIRM Board Approves Clinical Trials Targeting COVID-19 and Sickle Cell Disease

Coronavirus particles, illustration.

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved new clinical trials for COVID-19 and sickle cell disease (SCD) and two earlier stage projects to develop therapies for COVID-19.

Dr. Michael Mathay, of the University of California at San Francisco, was awarded $750,000 for a clinical trial testing the use of Mesenchymal Stromal Cells for respiratory failure from Acute Respiratory Distress Syndrome (ARDS). In ARDS, patients’ lungs fill up with fluid and are unable to supply their body with adequate amounts of oxygen. It is a life-threatening condition and a major cause of acute respiratory failure. This will be a double-blind, randomized, placebo-controlled trial with an emphasis on treating patients from under-served communities.

This award will allow Dr. Matthay to expand his current Phase 2 trial to additional underserved communities through the UC Davis site.

“Dr. Matthay indicated in his public comments that 12 patients with COVID-related ARDS have already been enrolled in San Francisco and this funding will allow him to enroll more patients suffering from COVID- associated severe lung injury,” says Dr. Maria T. Millan, CIRM’s President & CEO. “CIRM, in addition to the NIH and the Department of Defense, has supported Dr. Matthay’s work in ARDS and this additional funding will allow him to enroll more COVID-19 patients into this Phase 2 blinded randomized controlled trial and expand the trial to 120 patients.”

The Board also approved two early stage research projects targeting COVID-19.

  • Dr. Stuart Lipton at Scripps Research Institute was awarded $150,000 to develop a drug that is both anti-viral and protects the brain against coronavirus-related damage.
  • Justin Ichida at the University of Southern California was also awarded $150,00 to determine if a drug called a kinase inhibitor can protect stem cells in the lungs, which are selectively infected and killed by the novel coronavirus.

“COVID-19 attacks so many parts of the body, including the lungs and the brain, that it is important for us to develop approaches that help protect and repair these vital organs,” says Dr. Millan. “These teams are extremely experienced and highly renowned, and we are hopeful the work they do will provide answers that will help patients battling the virus.”

The Board also awarded Dr. Pierre Caudrelier from ExcellThera $2 million to conduct a clinical trial to treat sickle cell disease patients

SCD is an inherited blood disorder caused by a single gene mutation that results in the production of “sickle” shaped red blood cells. It affects an estimated 100,000 people, mostly African American, in the US and can lead to multiple organ damage as well as reduced quality of life and life expectancy.  Although blood stem cell transplantation can cure SCD fewer than 20% of patients have access to this option due to issues with donor matching and availability.

Dr. Caudrelier is using umbilical cord stem cells from healthy donors, which could help solve the issue of matching and availability. In order to generate enough blood stem cells for transplantation, Dr. Caudrelier will be using a small molecule to expand these blood stem cells. These cells would then be transplanted into twelve children and young adults with SCD and the treatment would be monitored for safety and to see if it is helping the patients.

“CIRM is committed to finding a cure for sickle cell disease, the most common inherited blood disorder in the U.S. that results in unpredictable pain crisis, end organ damage, shortened life expectancy and financial hardship for our often-underserved black community” says Dr. Millan. “That’s why we have committed tens of millions of dollars to fund scientifically sound, innovative approaches to treat sickle cell disease. We are pleased to be able to support this cell therapy program in addition to the gene therapy approaches we are supporting in partnership with the National Heart, Lung and Blood Institute of the NIH.”

Promising results from CIRM-funded projects

Severe Leukocyte Adhesion Deficiency-1 (LAD-1) is a rare condition that causes the immune system to malfunction and reduces its ability to fight off viruses and bacteria. Over time the repeated infections can take a heavy toll on the body and dramatically shorten a person’s life. But now a therapy, developed by Rocket Pharmaceuticals, is showing promise in helping people with this disorder.

The therapy, called RP-L201, targets white blood cells called neutrophils which ordinarily attack and destroy invading particles. In people with LAD-1 their neutrophils are dangerously low. That’s why the new data about this treatment is so encouraging.

In a news release, Jonathan Schwartz, M.D., Chief Medical Officer of Rocket, says early results in the CIRM-funded clinical trial, show great promise:

“Patients with severe LAD-I have neutrophil CD18 expression of less than 2% of normal, with extremely high mortality in early childhood. In this first patient, an increase to 47% CD18 expression sustained over six months demonstrates that RP-L201 has the potential to correct the neutrophil deficiency that is the hallmark of LAD-I. We are also pleased with the continued visible improvement of multiple disease-related skin lesions. The second patient has recently been treated, and we look forward to completing the Phase 1 portion of the registrational trial for this program.”

The results were released at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy.

=================================================

These microscopic images show gene expression in muscle stem and progenitor cells as they mature from early development to adulthood (left to right). As part of this process, the cells switch from actively expressing one key gene (green) to another (violet); this is accompanied by the growth of muscle fibers (red).
Photo courtesy: Cell Stem Cell/UCLA Broad Stem Cell Research Center

When you are going on a road-trip you need a map to help you find your way. It’s the same with stem cell research. If you are going to develop a new way to treat devastating muscle diseases, you need to have a map to show you how to build new muscle stem cells. And that’s what researchers at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA – with help from CIRM funding – have done.

The team took muscle progenitor cells – which show what’s happening in development before a baby is born – and compared them to muscle stem cells – which control muscle development after a baby is born. That enabled them to identify which genes are active at what stage of development.

In a news release, April Pyle, senior author of the paper, says this could open the door to new therapies for a variety of conditions:

“Muscle loss due to aging or disease is often the result of dysfunctional muscle stem cells. This map identifies the precise gene networks present in muscle progenitor and stem cells across development, which is essential to developing methods to generate these cells in a dish to treat muscle disorders.”

The study is published in the journal Cell Stem Cell.

A clear vision for the future

Dr. Henry Klassen and Dr. Jing Yang, founders of jCyte

When you have worked with a group of people over many years the relationship becomes more than just a business venture, it becomes personal. That’s certainly the case with jCyte, a company founded by Drs. Henry Klassen and Jing Yang, aimed at finding a cure for a rare form of vision loss called retinitis pigmentosa. CIRM has been supporting this work since it’s early days and so on Friday, the news that jCyte has entered into a partnership with global ophthalmology company Santen was definitely a cause for celebration.

The partnership could be worth up to $252 million and includes an immediate payment of $62 million. The agreement also connects jCyte to Santen’s global business and medical network, something that could prove invaluable in bringing their jCell therapy to patients outside the US.

Here in the US, jCyte is getting ready to start a Phase 2 clinical trial – which CIRM is funding – that could prove pivotal in helping it get approval from the US Food and Drug Administration.

As Dr. Maria Millan, CIRM’s President and CEO says, we have been fortunate to watch this company steadily progress from having a promising idea to developing a life-changing therapy.

“This is exciting news for everyone at jCyte. They have worked so hard over many years to develop their therapy and this partnership is a reflection of just how much they have achieved. For us at CIRM it’s particularly encouraging. We have supported this work from its early stages through clinical trials. The people who have benefited from the therapy, people like Rosie Barrero, are not just patients to us, they have become friends. The people who run the company, Dr. Henry Klassen, Dr. Jing Yang and CEO Paul Bresge, are so committed and so passionate about their work that they have overcome many obstacles to bring them here, an RMAT designation from the Food and Drug Administration, and a deal that will help them advance their work even further and faster. That is what CIRM is about, following the science and the mission.”

Paul Bresge, jCyte’s CEO says they couldn’t have done it without CIRM’s early and continued investment.

Paul Bresge, jCyte CEO

“jCyte is extremely grateful to CIRM, which was established to support innovative regenerative medicine programs and research such as ours.  CIRM supported our early preclinical data all the way through our late stage clinical trials.  This critical funding gave us the unique ability and flexibility to put patients first in each and every decision that we made along the way. In addition to the funding, the guidance that we have received from the CIRM team has been invaluable. jCell would not be possible without the early support from CIRM, our team at jCyte, and patients with degenerative retinal diseases are extremely appreciative for your support.”

Here is Rosie Barrero talking about the impact jCell has had on her life and the life of her family.

A true Hall of Fame winner

Dr. Larry Goldstein: Photo courtesy UCSD

You know you are working with some of the finest scientific minds in the world when they get elected to the prestigious National Academy of Sciences (NAS). It’s the science equivalent of the baseball, football or even Rock and Roll Hall of Fame. People only get in if their peers vote them in. It’s considered one of the highest honors in science, one earned over many decades of hard work. And when it comes to hard work there are few people who work harder than U.C. San Diego’s Dr. Lawrence Goldstein, one of the newly elected members of the NAS.

Dr. Goldstein – everyone calls him Larry – was the founder and director of the UCSD Stem Cell Program and the Sanford Stem Cell Clinical Center at UC San Diego Health and is founding scientific director of the Sanford Consortium for Regenerative Medicine.

For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.

In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.

His work has also helped develop a deeper understanding of the genetics of Alzheimer’s and to identify possible new targets for stem cell and other therapies.

Larry was typically modest when he heard the news, saying: “I have been very fortunate to have wonderful graduate students and fellows who have accomplished a great deal of excellent research. It is a great honor for me and for all of my past students and fellows – I am obviously delighted and hope to contribute to the important work of the National Academy of Sciences.”

But Larry doesn’t intend to rest on his laurels. He says he still has a lot of work to do, including “raising funding to test a new drug approach for Alzheimer’s disease that we’ve developed with CIRM support.”

Jennifer Briggs Braswell, PhD, worked with Larry at UCSD from 2005 to 2018. She says Larry’s election to the NAS is well deserved:

“His high quality publications, the pertinence of his studies in neurodegeneration to our current problems, and his constant, unwavering devotion to the next generation of scientists is matched only by his dedication to improving public understanding of science to motivate social, political, and financial support.  

“He has been for me a supportive mentor, expressing enthusiastic belief in the likely success of my good ideas and delivering critique with kindness and sympathy.   He continues to inspire me, our colleagues at UCSD and other communities, advocate publicly for the importance of science, and work tirelessly on solutions for neurodegenerative disorders.”

You can read about Larry’s CIRM-supported work here.

You can watch an interview with did with Larry a few years ago.

Huge honor, hugely deserved for CIRM-funded stem cell researcher

Dr. Andy McMahon: Photo courtesy USC

Andy McMahon is one of the most understated, humble and low-key people you are ever likely to meet. He’s also one of the smartest. And he has a collection of titles to prove it. He is the W.M. Keck Provost and University Professor in USC’s departments of Stem Cell Biology and Regenerative Medicine at the Keck School of Medicine, and Biological Sciences at the Dornsife College of Letters, Arts and Sciences, a fellow of the American Association for the Advancement of Science, the American Academy of Arts and Sciences, the European Molecular Biology Organization, and the Royal Society.

Now you can add to that list that Andy is a member of the National Academy of Sciences (NAS). Election to the NAS is no ordinary honor. It’s one of the highest in the scientific world.

In a USC news release Dean Laura Mosqueda from the Keck School praised Andy saying: “We’re delighted that Dr. McMahon is being recognized as a newly elected member of the National Academy of Sciences. Because new members are elected by current members, this represents recognition of Dr. McMahon’s achievements by his most esteemed peers in all scientific fields.”

Not surprisingly CIRM has funded some of Andy’s work – well, we do pride ourselves on working with the best and brightest scientists – and that research is taking on added importance with the spread of COVID-19. Andy’s area of specialty is kidneys, trying to develop new ways to repair damaged or injured kidneys. Recent studies show that between 3 and 9 percent of patients with COVID-19 develop an acute kidney injury; in effect their kidneys suddenly stop working and many of these patients have to undergo dialysis to stay alive.

Even those who recover are at increased risk for developing more chronic, even end-stage kidney disease. That’s where Andy’s work could prove most useful. His team are using human stem cells to create mini artificial kidneys that have many of the same properties as the real thing. These so-called “organoids” enable us to study chronic kidney disease, come up with ideas to repair damage or slow down the progression of the disease, even help improve the chances of a successful transplant if that becomes necessary.

You can hear Andy talk about his work here:

CIRM is now funding a number of projects targeting COVID-19, including a clinical trial using convalescent plasma gel, and intends investing in more in the coming weeks and months. You can read about that here.

We are also funding several clinical trials targeting kidney failure. You can read about those on our Clinical Trials Dashboard page – diseases are listed alphabetically.

Treatment for heart failure shows promising results for COVID-19 patients

Dr. Linda Marbán

To help with the coronavirus pandemic, many scientists are repurposing previously developed approaches or treatments to see if they can be used to treat patients with COVID-19. Capricor Therapeutics, lead by Dr. Linda Marbán, is using cardiosphere derived cells (CDCs), which are stem cells derived from heart tissue, to treat critically ill patients with COVID-19.

When a patient contracts the virus, their body produces cytokines, proteins that play an important role in the immune response. Unfortunately, having too many cytokines, known as a “cytokine storm”, leads to a severe immune reaction that can cause pneumonia, organ failure, and death. CDCs in previous studies have been shown to help regulate the immune response and cytokines, which could help patients with COVID-19.

Over the course of one month, six critically ill patients with COVID-19, five of whom were on mechanical ventilators, were treated with CDCs. In these compassionate care cases, five male patients and one female patient received treatment. Of the five patients on ventilator support, four patients no longer required ventilator support within just one to four days after treatment. Although these results are promising, it is important to remember that this treatment is in very early testing and will need to demonstrate significant improvement in larger patient groups.

Following a review of the results of this small study, the U.S. Food and Drug Administration (FDA) approved treatment of up to an 20 additional COVID-19 patients.

In a press release, Dr. Marbán discuses the results of the compassionate care study and treatment of additional COVID-19 patients.

“As the global medical community continues to come together in its battle against COVID-19, the results of our initial compassionate care cases are extremely promising and what we had anticipated. We look forward to continuing to treat additional patients under our recently approved expanded access program Investigational New Drug application.” 

The treatment used was developed with the help of a CIRM funded preclinical study. It has also been used in three CIRM funded clinical trials for heart disease associated with duchenne muscular dystrophy, heart failure, and pulmonary arterial hypertension.

Stem Cells for Parkinson’s Disease

While the world has been turned upside down by the coronavirus pandemic, the virus poses an increased threat to people with Parkinson’s disease (PD). Having a compromised immune system, particularly involving the lungs, means people with PD are at higher risk of some of the more dangerous complications of COVID-19. So, this seems like an appropriate time for CIRM to hold a special Facebook Live “Ask the Stem Cell Team” About Parkinson’s disease.

We are holding the event on Tuesday, May 5th at noon PDT.

The initial reason for the Facebook Live was the CIRM Board approving almost $8 million for Dr. Krystof Bankiewicz at Brain Neurotherapy Bio, Inc. to run a Phase 1 clinical trial targeting PD. Dr. Bankiewicz is using a gene therapy approach to promote the production of a protein called GDNF, which is best known for its ability to protect dopaminergic neurons, the kind of cell damaged by Parkinson’s. The approach seeks to increase dopamine production in the brain, alleviating PD symptoms and potentially slowing down the disease progress.

Dr. Bankiewicz will be joined by two of CIRM’s fine Science Officers, Dr. Lila Collins and Dr. Kent Fitzgerald. They’ll talk about the research targeting Parkinson’s that CIRM is funding plus other promising research taking place.

And we are delighted to have a late addition to the team. Our CIRM Board member and patient advocate for Parkinson’s disease, Dr. David Higgins. David has a long history of advocacy for PD and adds the invaluable perspective of someone living with PD.

As always, we want this to be as interactive as possible, so we want to get your questions. You can do this on the day, posting them alongside the live feed, or you can send them to us ahead of time at info@cirm.ca.gov. We’ll do our best to answer as many as we can on the day, and those we don’t get to during the broadcast we’ll answer in a later blog.

We look forward to seeing you there.

Two UCLA scientists receive CIRM funding for discovery research for COVID-19

Dr. Brigitte Gomperts (left) and Dr. Gay Crooks (right), UCLA
Image Credit: UCLA Broad Stem Cell Center

This past Friday, the CIRM Board approved funding for its first clinical study for COVID-19. In addition to this, the Board also approved two discovery stage research projects, which support promising new technologies that could be translated to enable broad use and improve patient care. Before we go into more detail, the two awards are summarized in the table below:

The discovery grant for $150,000 was given to Dr. Gay Crooks at UCLA to study how specific immune cells called T cells respond to COVID-19. The goal of this is to inform the development of vaccines and therapies that harness T cells to fight the virus. Typically, vaccine research involves studying the immune response using cells taken from infected people. However, Dr. Crooks and her team are taking T cells from healthy people and using them to mount strong immune responses to parts of the virus in the lab. They will then study the T cells’ responses in order to better understand how T cells recognize and eliminate the virus.

This method uses blood forming stem cells and then converts them into specialized immune cells called dendritic cells, which are able to devour proteins from viruses and chop them into fragments, triggering an immune response to the virus.

In a press release from UCLA, Dr. Crooks says that, “The dendritic cells we are able to make using this process are really good at chopping up the virus, and therefore eliciting a strong immune response”

The discovery grant for $149,998 was given to Dr. Brigitte Gomberts at UCLA to study a lung organoid model made from human stem cells in order to identify drugs that can reduce the number of infected cells and prevent damage in the lungs of patients with COVID-19. Dr. Gomberts will be testing drugs that have been approved by the U.S. Food and Drug Administration (FDA) for other purposes or have been found to be safe in humans in early clinical trials. This increases the likelihood that if a successful drug is found, it can be approved more rapidly for widespread use.

In the same press release from UCLA, Dr. Gomberts discusses the potential drugs they are evaluating.

“We’re starting with drugs that have already been tested in humans because our goal is to find a therapy that can treat patients with COVID-19 as soon as possible.”

CIRM Board Funds its First Clinical Study for COVID-19

Dr. John Zaia, City of hope

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) continued its commitment to help with the coronavirus pandemic by awarding $749,999 to Dr. John Zaia at City of Hope.  He will be conducting a clinical study to administer blood plasma from recovered COVID-19 patients to treat those with the virus.  This marks CIRM’s first clinical study for COVID-19 after approving emergency funding a month earlier.

Plasma is a component of blood that carries proteins called antibodies that are usually involved in defending our bodies against viral infections.  Blood plasma from patients that have recovered from COVID-19, referred to as convalescent plasma, contain antibodies against the virus that can be used as a potential treatment for COVID-19.  Currently, there are challenges with this approach that include: properly identifying convalescent plasma donors i.e. recovered patients, determining eligibility of those with convalescent plasma that want to donate, collection of the plasma, treating patients, and determining if the plasma was effective.

Dr. Zaia and his team at City of Hope will create the COVID-19 Coordination Program, which addresses solutions for all of the challenges listed above. The program will partner with the medical teams at CIRM’s Alpha Stem Cell Clinic Network, as well as infectious disease, pulmonary and critical care teams from medical centers and community hospitals across the state.  Potential donors will be identified and thoroughly screened for eligibility per the established National and State blood banking safety requirements. Finally, the convalescent plasma will be collected from eligible donors and administered by licensed physicians to COVID-19 patients, who will be evaluated for response to the treatment and potential recovery.

“We are in the midst of very challenging times where there is not yet an approved treatment for COVID-19. In response to this, CIRM launched and executed an emergency COVID-19 funding program, which was made possible by our Board, patient advocates, California scientists, external scientific expert reviewers, and our dedicated team,” said Maria T. Millan, MD, President and CEO of CIRM. “With CIRM funding, the City of Hope COVID-19 Coordination program will tap into CIRM’s network of researchers, physicians, and our Alpha Clinics to deliver this treatment to patients in need.  It will also serve the critical role of gathering important scientific data about the plasma, safety, and clinical data from treated patients.”

The Board also approved a discovery stage research project that utilizes stem cell models for a novel approach to vaccine development against the virus causing COVID-19 and another project that uses a unique lung stem cell organoid to identify an effective drug against the virus.

The two awards are summarized in the table below:

Helping the blind see – mice that is

When I first saw the headline for this story I thought of the nursery rhyme about the three blind mice. Finally, they’ll be able to see the farmer’s wife coming at them with a carving knife. But the real-world implications are of this are actually pretty exciting.

Researchers at the National Institute of Health’s National Eye Institute took skin cells from mice and directly reprogrammed them into becoming light sensitizing cells in the eye, the kind that are often damaged and destroyed by diseases like macular degeneration or retinitis pigmentosa.

What’s particularly interesting about this is that it bypassed the induced pluripotent stem cell (iPSC) stage where researchers turn the skin cells into embryonic-like cells, then turn those into the cells found in the eye.

In a news release, Anand Swaroop of the NEI says this more direct approach has a number of advantages: “This is the first study to show that direct, chemical reprogramming can produce retinal-like cells, which gives us a new and faster strategy for developing therapies for age-related macular degeneration and other retinal disorders caused by the loss of photoreceptors.”

After converting the skin cells into cells called rod photoreceptors – the light sensing cells found in the back of the eye – the team transplanted them into blind mice. One month later they tested the mice to see if there had been any change in vision. There had; 43 percent of the mice reacted to light exposure, something they hadn’t done before.

Biraj Mahato, the study’s first author, said that three months later, the transplanted cells were still alive and functioning. “Even mice with severely advanced retinal degeneration, with little chance of having living photoreceptors remaining, responded to transplantation. Such findings suggest that the observed improvements were due to the lab-made photoreceptors rather than to an ancillary effect that supported the health of the host’s existing photoreceptors.”

Obviously there is a lot of work still to do before we can even begin to think about trying something like this in people. But this is certainly an encouraging start.

In the meantime, CIRM is funding a number of stem cell programs aimed at treating vision destroying diseases like macular degeneration and retinitis pigmentosa.