Funding a Clinical Trial for a Functional Cure for HIV

The use of antiretroviral drugs has turned HIV/AIDS from a fatal disease to one that can, in many cases in the US, be controlled. But these drugs are not a cure. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) voted to approve investing $6.85 million in a therapy that aims to cure the disease.

This is the 82nd clinical trial funded by CIRM.

There are approximately 38 million people worldwide living with HIV/AIDS. And each year there are an estimated 1.5 million new cases. The vast majority of those living with HIV do not have access to the life-saving antiretroviral medications that can keep the virus under control. People who do have access to the medications face long-term complications from them including heart disease, bone, liver and kidney problems, and changes in metabolism.

The antiretroviral medications are effective at reducing the viral load in people with HIV, but they don’t eliminate it. That’s because the virus that causes AIDS can integrate its DNA into long-living cells in the body and remain dormant. When people stop taking their medications the virus is able to rekindle and spread throughout the body.

Dr. William Kennedy and the team at Excision Bio Therapeutics have developed a therapeutic candidate called EBT-101. This is the first clinical study using the CRISPR-based platform for genome editing and excision of the latent form of HIV-1, the most common form of the virus that causes AIDS in the US and Europe. The goal is to eliminate or sufficiently reduce the hidden reservoirs of virus in the body to the point where the individual is effectively cured.

“To date only a handful of people have been cured of HIV/AIDS, so this proposal of using gene editing to eliminate the virus could be transformative,” says Dr. Maria Millan, President and CEO of CIRM. “In California alone there are almost 140,000 people living with HIV. HIV infection continues to disproportionately impact marginalized populations, many of whom are unable to access the medications that keep the virus under control. A functional cure for HIV would have an enormous impact on these communities, and others around the world.”

In a news release announcing they had dosed the first patient, Daniel Dornbusch, CEO of Excision, called it a landmark moment. “It is the first time a CRISPR-based therapy targeting an infectious disease has been administered to a patient and is expected to enable the first ever clinical assessment of a multiplexed, in vivo gene editing approach. We were able to reach this watershed moment thanks to years of innovative work by leading scientists and physicians, to whom we are immensely grateful. With this achievement, Excision has taken a major step forward in developing a one-time treatment that could transform the HIV pandemic by freeing affected people from life-long disease management and the stigma of disease.”

The Excision Bio Therapeutics team also scored high on their plan for Diversity, Equity and Inclusion. Reviewers praised them for adding on a partnering organization to provide commitments to serve underserved populations, and to engaging a community advisory board to help guide their patient recruitment.

CIRM has already invested almost $81 million in 20 projects targeting HIV/AIDS, including four clinical trials.

Fast Track Designation for a therapy making transplants safer for children with a fatal immune disorder

Bone marrow transplant

For children born with severe combined immunodeficiency (SCID) life can be very challenging. SCID means they have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life.

There are stem cell/gene therapies funded by the California Institute for Regenerative Medicine (CIRM), such as ones at UCLA and UCSF/St. Judes, but an alternative method of treating, and even curing the condition, is a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s blood supply with one that is free of the SCID mutation, which helps restore their immune system.

However, current HCT methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.

To change that, Dr. Judy Shizuru at Stanford University, with CIRM funding, developed an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells, creating the room needed to transplant new, healthy cells. The goal was to make stem cell transplants safer and more effective for the treatment of many life-threatening blood disorders.

That approach, JSP191, is now being championed by Jasper Therapeutics and they just got some very good news from the Food and Drug Administration (FDA). The FDA has granted JSP191 Fast Track Designation, which can speed up the review of therapies designed to treat serious conditions and fill unmet medical needs.

In a news release, Ronald Martell, President and CEO of Jasper Therapeutics, said this is good news for the company and patients: “This new Fast Track designation recognizes the potential role of JSP191 in improving clinical outcomes for these patients and will allow us to more closely work with the FDA in the upcoming months to determine a path toward a Biologics License Application (BLA) submission.”

Getting a BLA means Jasper will be able to market the antibody in the US and make it available to all those who need it.

This is the third boost from the FDA for Jasper. Previously the agency granted JSP191 both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.

The race to cure sickle cell disease

September is National Sickle Cell Awareness Month, a time to refocus our efforts to find new treatments, even a cure, for people with sickle cell disease. Until we get those, CIRM remains committed to doing everything we can to reduce the stigma and bias that surrounds it.

Sickle cell disease (SCD) is a rare, inherited blood disorder in which normally smooth and round red blood cells may become sickle-shaped and harden. These blood cells can clump together and clog up arteries, causing severe and unpredictable bouts of pain, organ damage, vision loss and blindness, strokes and premature death.

There is a cure, a bone marrow transplant from someone who is both a perfect match and doesn’t carry the SCD trait. However, few patients are able to find that perfect match and even if they do the procedure carries risks.

That’s why the California Institute for Regenerative Medicine (CIRM) has invested almost $60 million in 14 projects, including five clinical trials targeting the disease. It’s also why we are partnering with the National Heart, Lung and Blood Institute (NHLBI) in their Cure Sickle Cell Initiative (CureSCi).

As part of the events around National Sickle Cell Awareness Month the NHLBI is launching the Gene Therapy to Reduce All Sickle Pain (GRASP) Trial and hosting a special Journeys in Mental Health Webinar on September 27th

The GRASP Trial is a Phase 2 trial that will take place at various locations throughout the country.  It’s a collaboration between the NHLBI and CIRM. Researchers are testing whether a gene therapy approach can improve or eliminate sickle cell pain episodes.  

Shortly after being born, babies stop producing blood containing oxygen-rich fetal hemoglobin and instead produce blood with the adult hemoglobin protein. For children with sickle cell disease, the transition from the fetal to the adult form of hemoglobin marks the onset of anemia and the painful symptoms of the disorder.

Scientists previously discovered that the BCL11A gene helps to control fetal hemoglobin and that decreasing the expression of this gene can increase the amount of fetal hemoglobin while at the same time reducing the amount of sickle hemoglobin in blood.  This could result in boosting the production of normal shaped red blood cells with a goal of curing or reducing the severity of sickle cell disease.   

The approach used in this trial is similar to a bone marrow transplant, but instead of using donor stem cells, this uses the patient’s own blood stem cells with new genetic information that instructs red blood cells to silence the expression of the BCL11A gene. This approach is still being studied to make sure that it is safe and effective, but it potentially has the advantage of eliminating some of the risks of other therapies. 

In this trial, patients will have to spend some time in an inpatient unit as they undergo chemotherapy to kill some bone marrow blood stem cells and create room for the new, gene-modified cells to take root.

The trial is based on a successful pilot/phase 1 study which showed it to be both safe and effective in the initial 10 patients enrolled in the trial.

For more information about the trial, including inclusion/exclusion criteria and trial locations, please visit the CureSCi GRASP trial page.

Nancy Rene, a sickle cell disease patient advocate, says while clinical trials like this are obviously important, there’s another aspect of the treatment of people with the disease that is still too often overlooked.

“As much as I applaud CIRM for the work they are doing to find a therapy or cure for Sickle Cell, I am often dismayed by the huge gulf between research protocols and general medical practice. For every story I hear about promising research, there is often another sad tale about a sickle cell patient receiving inadequate care. This shouldn’t be an either/or proposition. Let’s continue to support ground-breaking research while we expand education and training for medical professionals in evidenced based treatment. I look forward to the day when sickle cell patients receive the kind of treatment they need to lead healthy, pain-free lives.”

How stem cells helped Veronica fight retinitis pigmentosa and regain her vision

Veronica and Elliott

Growing up Veronica McDougall thought everyone saw the world the way she did; blurry, slightly out-of-focus and with tunnel vision.  As she got older her sight got worse and even the strongest prescription glasses didn’t help. When she was 15 her brother tried teaching her to drive. One night she got into the driver’s seat to practice and told him she couldn’t see anything. Everything was just black. After that she stopped driving.   

Veronica says high school was really hard for her, but she managed to graduate and go to community college. As her vision deteriorated, she found it was increasingly hard to read the course work and impossible to see the assignments on the blackboard. Veronica says she was lucky to have some really supportive teachers — including the now First Lady Jill Biden — but eventually she had to drop out.  

Getting a diagnosis

When she was 24, she went to see a specialist who told her she had retinitis pigmentosa, a rare degenerative condition that would eventually leave her legally blind. She says it felt like a death sentence. “All of my dreams of becoming a nurse, of getting married, of having children, of traveling – it all just shattered in that moment.” 

Veronica says she went from being a happy, positive person to an angry depressed one. She woke up each morning terrified, wondering, “Is this the day I go blind?” 

Then her mother learned about a CIRM-funded clinical trial with a company called jCyte. Veronica applied to be part of it, was accepted and was given an injection of stem cells in her left eye. She says over the course of a few weeks, her vision steadily improved. 

“About a month after treatment, I was riding in the car with my mom and suddenly, I realized I could see her out of the corner of my eye while looking straight ahead. That had never, ever happened to me before. Because, I had been losing my peripheral vision at a young age without realizing that until up to that point, I had never had that experience.” 

A second chance at life

She went back to college, threw herself into her studies, started hiking and being more active. She says it was as if she was reborn. But in her senior year, just as she was getting close to finishing her degree, her vision began to deteriorate again. Fortunately, she was able to take part in a second clinical trial, and this time her vision came back stronger than ever. 

“I’m so grateful to the researchers who gave me my sight back with the treatment they have worked their entire lives to develop. I am forever grateful for the two opportunities to even receive these two injections and to be a part of an amazing experience to see again. I feel so blessed! Thank you for giving me my life back.” 

And in getting her life back, Veronica had a chance to give life. When she was at college she met and starting dating Robert, the man who was to become her partner. They now have a little boy, Elliott.  

As for the future, Veronica hopes to get a second stem cell therapy to improve her vision even further. Veronica’s two treatments were in her left eye. She is hoping that the Food and Drug Administration will one day soon approve jCyte’s therapy, so that she can get the treatment in her right eye. Then, she says, she’ll be able to see the world as the rest of us can.  

CIRM has invested more than $150 million in programs targeting vision loss, including four clinical trials for retinitis pigmentosa

A better, faster, more effective way to edit genes

Clinical fellow Brian Shy talks with postdoctoral scholar Tori Yamamoto in the Marson Lab at Gladstone Institutes on June 8th, 2022. Photo courtesy Gladstone Institutes.

For years scientists have been touting the potential of CRISPR, a gene editing tool that allows you to target a specific mutation and either cut it out or replace it with the corrected form of the gene. But like all new tools it had its limitations. One important one was the difficult in delivering the corrected gene to mature cells in large numbers.

Scientists at the Gladstone Institutes and U.C. San Francisco say they think they have found a way around that. And the implications for using this technique to develop new therapies for deadly diseases are profound.

In the past scientists used inactivated viruses as a way to deliver corrected copies of the gene to patients. We have blogged about UCLA’s Dr. Don Kohn using this approach to treat children born with SCID, a deadly immune disorder. But that was both time consuming and expensive.

CRISPR, on the other hand, showed that it could be easier to use and less expensive. But getting it to produce enough cells for an effective therapy proved challenging.

The team at Gladstone and UCSF found a way around that by switching from using CRISPR to deliver a double-stranded DNA to correct the gene (which is toxic to cells in large quantities), and instead using CRISPR to deliver a single stranded DNA (you can read the full, very technical description of their approach in the study they published in the journal Nature Biotechnology).

Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and the senior author of the study, said this more than doubled the efficiency of the process. “One of our goals for many years has been to put lengthy DNA instructions into a targeted site in the genome in a way that doesn’t depend on viral vectors. This is a huge step toward the next generation of safe and effective cell therapies.”

It has another advantage too, according to Gladstone’s Dr. Jonathan Esensten, an author of the study. “This technology has the potential to make new cell and gene therapies faster, better, and less expensive.”

The team has already used this method to generate more than one billion CAR-T cells – specialized immune system cells that can target cancers such as multiple myeloma – and says it could also prove effective in targeting some rare genetic immune diseases.

The California Institute for Regenerative Medicine (CIRM) helped support this research. Authors Brian Shy and David Nguyen were supported by the CIRM:UCSF Alpha Stem Cell Clinic Fellowship program.

Stem Cell Agency Expands Industry Alliance Program to  Accelerate Therapies

An ever-growing array of academic and industry resources are required to rapidly translate scientific discoveries and emerging technologies toward safe and effective regenerative medicine therapies for patients. To help, the California Institute for Regenerative Medicine (CIRM) is creating a network of Industry Resource Partners (IRP) that will make its unique resources available to help accelerate the progression of CIRM-funded Discovery, Translational and Clinical stage research projects toward transformative regenerative medicine therapies for rare and prevalent diseases.

The Industry Resource Partners will offer their services, technologies and expertise to CIRM-funded projects in a cost-effective, stage-appropriate and consistent manner.

For example, Novo Nordisk is making research-grade vials of its Good Manufacturing Practice (GMP)-grade human embryonic stem cell line available for CIRM Discovery Quest stage research projects at no cost. Having access to clinically compatible pluripotent stem cell lines such as this one will help CIRM researchers accelerate the translation of their therapeutic discoveries toward clinical use. Researchers will also have future access to Novo Nordisk’s GMP seed stock as well as opportunities for partnering with Novo Nordisk.

“CIRM is a lender of first resort, supporting projects in the very early stages, long before they are able to attract outside investment,” says Shyam Patel, PhD, the Director of Business Development at CIRM. “With the launch of this program we hope to create a force-multiplier effect by bringing in industry partners who have the resources, experience and expertise to help further accelerate CIRM-funded regenerative medicine research projects.”

This new network builds on work CIRM started in 2018 with the Industry Alliance Program (IAP). The goal of the IAP was to partner researchers and industry to help accelerate the most promising stem cell, gene and regenerative medicine therapy programs to commercialization. Four of the members of the IAP are also founding members or the IRP.

In addition to Novo Nordisk, the IRP includes:

ElevateBio is providing access to high quality, well-characterized induced pluripotent stem cell (iPSC) lines to CIRM Discovery Quest stage research projects for product development in regenerative medicine. CIRM awardees will also have access to ElevateBio’s viral vector technologies, process development, analytical development, and GMP manufacturing services.

Bayer is offering to support the cell therapy process development and GMP manufacturing needs of CIRM Translational and Clinical awardees at its newly built Berkeley facilities. The partnered projects will have access to Bayer’s cell therapy manufacturing facilities, equipment, resources and expertise. Bayer is also open to partnering from fee-based-services to full business development and licensing opportunities. 

Resilience is providing access to its GMP manufacturing services for CIRM Translational and Clinical Stage projects. In addition to providing access to its cell therapy manufacturing services and partnering opportunities, Resilience will provide project consultation that could aid CIRM applicants in drafting manufacturing plans and budgets for CIRM applications.

“These partnerships are an important step forward in helping advance not only individual projects but also the field as a whole,” says Dr. Maria T. Millan, President and CEO of CIRM. “One of the biggest challenges facing regenerative medicine right now involves manufacturing. Providing researchers with access to high quality starting materials and advanced manufacturing capabilities is going to be essential in helping these projects maintain high quality standards and comply with the regulatory frameworks needed to bring these therapies to patients.”

While the IRP Network will offer its services to CIRM grantees there is no obligation or requirement that any CIRM awardee take advantage of these services.

The researcher who is following her bliss, and tackling diseases of aging at the same time

Dr. Jill Helms, and associate! Photo courtesy Stanford University

Jill Helms is not your average Stanford University faculty member. Yes, she is a professor in the Department of Surgery. Yes, she has published lots of scientific studies. Yes, she is a stem cell scientist (funded by CIRM). And yes, she is playing a leading role in Ankasa Regenerative Therapeutics, a company focused on tissue repair and regeneration. But she is so much more than all that.  

She is a brilliant public speaker, a fashionista, and has ridden her horse to work (well, Stanford is referred to as The Farm, so why not!) and she lives on a farm of her own called “Follow Your Bliss.” The name comes from philosopher Joseph Campbell who wrote, “If you follow your bliss, you put yourself on a kind of path that has been there all the while, waiting for you. And the life you ought to be living is the one you are living.”  

Dr. Helms says that pretty much sums up her life. She says she feels enormously blessed.  

Well, we felt enormously blessed when she agreed to sit down with us and chat about her work, her life and her love of fashion for the California Institute for Regenerative Medicine podcast, Talking ‘Bout (re)Generation.  

We hope you enjoy the latest episode! 

A grandmother’s legacy, a stem cell scientist

Emily Smith, CIRM Bridges student

The California Institute for Regenerative (CIRM) has a number of education programs geared towards training the next generation of stem cell and gene therapy researchers. Each student comes to the program with their own motivation, their own reasons for wanting to be a scientist. This is Emily Smith’s story.


Surrounded by the cold white walls of a hospital room, my family suddenly found themselves on the other side of medicine. Void of any answers or cures, this new reality was full of doubt. As we witnessed assurance dwindle into a look of angst, the doctor’s lips stiffened as he faltered to say the words that would change my grandmother’s life forever. The spinal cancer they had gone in to extract was a misdiagnosed nothing. Instead, the exploration of his scalpel left her paralyzed from the chest down.

Seemingly simple day-to-day moments of my life became the building blocks of my passion for science today. Early realizations of the hurdles laced throughout my grandmother’s life. Vivid memories of my mother’s weary smile as she read articles on the newest advancements in stem cell research. Collectively, what these fragments of time nurtured was hope. I grew to have a dream that something different awaited us in the future. With purpose, I dove into the world of research as an undergraduate.

Today, I am a CIRM Bridges to Stem Cell Research Intern at the Sanford Consortium for Regenerative Medicine. I received my acceptance into the program about a month after my grandmother’s passing. She never saw a cure, let alone an effective treatment.

My position allows me to understand why stem cell research takes time. The road from the bench to the clinic is a painstakingly deliberate one. And although we seek reason and order from the world of science, what we often find is how imperfect it all can be. At its root, I found that research is truly a human endeavor. That is why, as scientists, we must grapple with our lack of knowledge and failures with humility.

CIRM’s programs that train tomorrow’s scientists, such as Bridges, are important because they do more than simply transfer over skills from one generation to the next. Over the next year, I get the valuable experience of working with scientists who share a common dream. They understand the urgency of their research, value the quality of their findings, and put patient needs first. This mentorship ensures that a sense of responsibility is carried on throughout this field.

I applied to this program because stem cell research gave my family the gift of hope. Now, on the other side of the wait, I wish to serve patients and families like my own. I am incredibly grateful to be a part of the Bridges program and I will devote the full extent of my knowledge towards the advancement of this field.

How CIRM contributed to City of Hope study helping man with HIV into long-term remission

The news that a stem cell transplant at City of Hope helped a man with HIV go into long-term remission made banner headlines around the world. As it should. It’s a huge achievement, particularly as the 66-year-old man had been living with HIV since 1988.

What wasn’t reported was that work supported by the California Institute for Regenerative Medicine played a role in making that happen.

The Stem Cell Transplant

First the news. In addition to living with HIV the man was diagnosed with acute leukemia. Doctors at City of Hope found a donor who was not only a perfect match to help battle the patient’s leukemia, but the donor also had a rare genetic mutation that meant they were resistant to most strains of HIV.

In transplanting blood stem cells from the donor to the patient they were able to send both his leukemia and HIV into remission. The patient stopped taking all his antiretroviral medications 17 months ago and today has no detectable levels of HIV.

In a news release  City of Hope hematologist Ahmed Aribi, M.D., said the patient didn’t experience any serious complications after the procedure.

“This patient had a high risk for relapsing from AML [acute myeloid leukemia], making his remission even more remarkable and highlighting how City of Hope provides excellent care treating complicated cases of AML and other blood cancers.”

It’s a remarkable achievement and is only the fifth time that a patient with both HIV and leukemia has been put into remission after a transplant from an HIV-resistant donor.

CIRM’s Contribution

So, what does that have to do with CIRM? Well, CIRM’s Alpha Clinics Network helped City of Hope get this case approved by an Institutional Review Board (IRB) and also helped in collecting and shipping the donor blood. In addition, part of the Alpha Clinics team at University of California San Diego helped with the reservoir analysis of blood and gut biopsies to check for any remaining signs of HIV.

It’s a reminder that this kind of achievement is a team effort and CIRM is very good at creating and supporting teams. The Alpha Clinics Network is a perfect example. We created it because there was a need for a network of world-class medical facilities with the experience and expertise to deliver a whole new kind of therapy. The Network has been remarkably successful in doing that with more than 200 clinical trials, taking care of more than 1,000 patients, and treating more than 40 different diseases.

This year our Board approved expanding the number of these clinics to better serve the people of California.

While the role of the Alpha Clinics Network in helping this one patient may seem relatively small, it was also an important one. And we are certainly not stopping here. We have invested more than $79 million in 19 different projects targeting HIV/AIDS, include four clinical trials.

We are in this for the long term and results like the man who had HIV and is now in remission are a sign we are heading in the right direction.

Stem Cell Agency funds clinical trial targeting scarred urethras

A urethral stricture is scarring of the tube that carries urine out of the body. If left untreated it can be intensely painful and lead to kidney stones and infections. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) is investing more than $3.8 million in a Phase 1 clinical trial to create a stem cell-based therapy for the condition.

This is the 81st clinical trial that CIRM has funded.

When a scar, or stricture, forms along the urethra it impedes the flow of urine and causes other complications. James Yoo, M.D., Ph.D., and his team at Wake Forest University Health Sciences will use epithelial and smooth muscle cells, taken from the patient’s bladder, and layer them on to a synthetic tubular scaffold. The tube will then be surgically implanted inside the urethra.

The goal is for the progenitor cells to support self-renewal of the tissue and for the entire structure to become integrated into the surrounding tissue and become indistinguishable from it, restoring normal urinary function. Dr. Yoo and his team believe their approach has the potential to be effective for at least a decade.

“While not immediately life-threatening, urethral strictures lead to multiple health complications that impair quality of life and predispose to kidney dysfunction,” says Dr. Maria T. Millan, President and CEO of CIRM. “Developing an effective and durable treatment would significantly impact lives and has the potential to decrease the cumulative healthcare costs of treating recurrent kidney stones, infections and downstream kidney complications, especially of long-segment urethral strictures.”