CIRM Board Approves Funding for New Clinical Trial Targeting Brain Tumors

The governing Board of the California Institute for Regenerative Medicine (CIRM) has awarded almost $12 million to carry out a clinical trial targeting brain tumors.

This brings the total number of CIRM funded clinical trials to 83.  

$11,999,984 was awarded to Dr. Jana Portnow at the Beckman Research Institute of City of Hope. They are using Neural stem cells (NSCs) as a form of delivery vehicle to carry a cancer-killing virus that specifically targets brain tumor cells.

Glioblastoma is the most common malignant primary brain tumor in adults and each year about 12,000 Americans are diagnosed. The 5-year survival rate is only about 10%.

The current standard of care involves surgically removing the tumor followed by radiation, chemotherapy, and alternating electric field therapy. Despite these treatments, survival remains low.

The award to Dr. Portnow will fund a clinical trial to assess the safety and effectiveness of this stem cell-based treatment for Glioblastoma.

The Board also awarded $3,111,467 to Dr. Boris Minev of Calidi Biotherapeutics. This award is in the form of a CLIN1 grant, with the goal of completing the testing needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial in people.

This project uses donor fat-derived mesenchymal stem cells that have been loaded with oncolytic virus to target metastatic melanoma, triple negative breast cancer, and advanced head & neck squamous cell carcinoma.

“There are few options for patients with advanced solid tumor cancers such as glioblastoma, melanoma, breast cancer, and head & neck cancer,” says Maria T. Millan, M.D., President and CEO of CIRM. “Surgical resection, chemotherapy and radiation are largely  ineffective in advanced cases and survival typically is measured in months. These new awards will support novel approaches to address the unmet medical needs of patients with these devastating cancers.”

The CIRM Board also voted to approve awarding $71,949,539 to expand the CIRM Alpha Clinics Network. The current network consists of six sites and the Board approved continued funding for those and added an additional three sites. The funding is to last five years.

The goal of the Alpha Clinics award is to expand existing capacities for delivering stem cell, gene therapies and other advanced treatment to patients. They also serve as a competency hub for regenerative medicine training, clinical research, and the delivery of approved treatments.

Each applicant was required to submit a plan for Diversity, Equity and Inclusion to support and facilitate outreach and study participation by underserved and disproportionately affected populations in the clinical trials they serve.

The successful applicants are:

ApplicationProgram TitleInstitution/Principal InvestigatorAmount awarded
INFR4-13579The Stanford Alpha Stem Cell ClinicStanford University – Matthew Porteus  $7,997,246  
INFR4-13581UCSF Alpha Stem Cell ClinicU.C. San Francisco – Mark Walters  $7,994,347  
INFR4-13586A comprehensive stem cell and gene therapy clinic to
advance new therapies for a diverse patient
population in California  
Cedars-Sinai Medical Center – Michael Lewis  $7,957,966    
INFR4-13587The City of Hope Alpha Clinic: A roadmap for equitable and inclusive access to regenerative medicine therapies for all Californians  City of Hope – Leo Wang  $8,000,000
INFR4-13596Alpha Stem Cell Clinic for Northern and Central California  U.C. Davis – Mehrdad Abedi  $7,999,997  
INFR4-13685Expansion of the Alpha Stem Cell and Gene Therapy Clinic at UCLA  U.C. Los Angeles – Noah Federman  $8,000,000
INFR4-13878Alpha Clinic Network Expansion for Cell and Gene Therapies  University of Southern California – Thomas Buchanan  $7,999,983  
INFR4-13952A hub and spoke community model to equitably deliver regenerative medicine therapies to diverse populations across four California counties  U.C. Irvine – Daniela Bota  $8,000,000
INFR4-13597UC San Diego Health CIRM Alpha Stem Cell Clinic  U.C. San Diego – Catriona Jamieson  $8,000,000

The Board also unanimously, and enthusiastically, approved the election of Maria Gonzalez Bonneville to be the next Vice Chair of the Board. Ms. Bonneville, the current Vice President of Public Outreach and Board Governance at CIRM, was nominated by all four constitutional officers: the Governor, the Lieutenant Governor, the Treasurer and the Controller.

In supporting the nomination, Board member Ysabel Duron said: “I don’t think we could do better than taking on Maria Gonzalez Bonneville as the Vice Chair. She is well educated as far as CIRM goes. She has a great track record; she is empathetic and caring and will be a good steward for the taxpayers to ensure the work we do serves them well.”

In her letter to the Board applying for the position, Ms. Bonneville said: “CIRM is a unique agency with a large board and a long history. With my institutional knowledge and my understanding of CIRM’s internal workings and processes, I can serve as a resource for the new Chair. I have worked hand-in-hand with both the Chair and Vice Chair in setting agendas, prioritizing work, driving policy, and advising accordingly.  I have worked hard to build trusted relationships with all of you so that I could learn and understand what areas were of the most interest and where I could help shed light on those particular programs or initiatives. I have also worked closely with Maria Millan for the last decade, and greatly enjoy our working relationship. In short, I believe I provide a level of continuity and expertise that benefits the board and helps in times of transition.”

In accepting the position Ms. Bonneville said: “I am truly honored to be elected as the Vice Chair for the CIRM Board. I have been a part of CIRM for 11 years and am deeply committed to the mission and this new role gives me an opportunity to help support and advance that work at an exciting time in the Agency’s life. There are many challenges ahead of us but knowing the Board and the CIRM team I feel confident we will be able to meet them, and I look forward to helping us reach our goals.”

Ms. Bonneville will officially take office in January 2023.

The vote for the new Chair of CIRM will take place at the Board meeting on December 15th.

Pioneering a new approach to HIV/AIDS

Dr. Steven Deeks. Photo courtesy UCSF

I’ve always been impressed by the willingness of individuals to step forward and volunteer for a clinical trial. Even more so when they are the first person ever to test a first-in-human therapy. They really are pioneers in helping advance a whole new approach to treating disease. 

That’s certainly the case for the first individual treated in a CIRM-funded clinical trial to develop a functional cure for HIV/AIDS. Caring Cross announced recently that they have dosed the first patient in the trial testing their anti-HIV duoCAR-T cell therapy.  

The trial is being led by UC San Francisco’s Dr. Steven Deeks and UC Davis’ Dr. Mehrdad Abedi. Their approach involves taking a patient’s own blood and extracting T cells, a type of immune cell.  The T cells are then genetically modified to express two different chimeric antigen receptors (CAR), which enable the newly created duoCAR-T cells to recognize and destroy HIV infected cells.  The modified T cells are then reintroduced back into the patient. 

The goal of this one-time therapy is to act as a long-term control of HIV with patients no longer needing to take anti-HIV medications. If it is successful it would be, in effect, a form of functional HIV cure.   

This first phase involves giving different patients different levels of the duoCAR-T therapy to determine the best dose, and to make sure it is safe and doesn’t cause any negative side effects.  

This is obviously just the first step in a long process, but it’s an important first step and certainly one worth marking. As Dr. Deeks said in the news release, “We have reached an important milestone with the dosing of the first participant in the Phase 1/2a clinical trial evaluating a potentially groundbreaking anti-HIV duoCAR-T cell therapy. Our primary goal for this clinical trial is to establish the safety of this promising therapeutic approach.” 

Dr. Abedi, echoed that saying. “The first participant was dosed with anti-HIV duoCAR-T cells at the UC Davis medical center in mid-August. There were no adverse events observed that were related to the product and the participant is doing fine.” 

This approach carries a lot of significance not just for people with HIV in the US, but also globally. If successful it could help address the needs of people who are not able to access antiretroviral therapies or for whom those medications are no longer effective.  

Today there are an estimated 38 million people living with HIV around the world. Every year some 650,000 people die from the disease.  

So far, some encouraging news for stem cell clinical trial treating epilepsy

Neurona Therapeutics is testing a new therapy for a drug-resistant form of epilepsy and has just released some encouraging early findings. The first patient treated went from having more than 30 seizures a month to just four seizures over a three-month period.

This clinical trial, funded by the California Institute for Regenerative Medicine (CIRM), is targeting  mesial temporal lobe epilepsy (MTLE), one of the most common forms of epilepsy. Because the seizures caused by MTLE are frequent, they can be particularly debilitating and increase the risk of a decreased quality of life, depression, anxiety and memory impairment.

Neurona’s therapy, called NRTX-1001, consists of a specialized type of neuronal cell derived from embryonic stem cells.  Neuronal cells are messenger cells that transmit information between different areas of the brain, and between the brain and the rest of the nervous system.

NRTX-1001 is injected into the brain in the area affected by the seizures where it releases neurotransmitters or chemical messengers that will block the signals in the brain causing the epileptic seizures.

The first patient treated had a nine-year history of epilepsy and, despite being on anti-epileptic medications, was experiencing dozens of seizures a month. Since the therapy he has had only four seizures in three months. The therapy hasn’t produced any serious side effects.

In a news release Dr. Cory Nicholas, Neurona’s President and CEO, said while this is only one patient, it’s good news.

“The reduced number of seizures reported by the first person to receive NRTX-1001 is very encouraging, and we remain cautiously optimistic that this reduction in seizure frequency will continue and extend to others entering this cell therapy trial. NRTX-1001 administration has been well tolerated thus far in the clinic, which is in line with the extensive preclinical safety data collected by the Neurona team. With recent clearance from the Data Safety Monitoring Board we are excited to continue patient enrollment. We are very grateful to these first participants, and thank the clinical teams for the careful execution of this pioneering study.”

CIRM has been a big supporter of this work from the early Discovery stage work to this clinical trial. That’s because when we find something promising, we want to do everything we can to help it live up to its promise.

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.

Stem Cell Agency Invests $46 Million in New Education Program

CIRM Bridges students 2022. The CIRM Board approved funding for a program to help even more students advance a career in science.

The governing Board of the California Institute for Regenerative Medicine (CIRM) has approved $46,076,430 to invest in its newest education pillar- the COMPASS (Creating Opportunities through Mentorship and Partnership Across Stem cell Science) training program.

Education is at the core of CIRM’s mission of accelerating world class science to deliver transformative regenerative medicine treatments in an equitable manner to a diverse California and world. And funding these additional programs is an important step in ensuring that California has a well-trained stem cell workforce.

The objective of COMPASS is to prepare a diverse cadre of undergraduate students for careers in regenerative medicine through combining hands-on research opportunities with strategic and structured mentorship experiences.

“Education and infrastructure are two funding pillars critical for creating the next generation of researchers and conducting stem cell based clinical trials,” says Jonathan Thomas, Ph.D., J.D., Chair of the CIRM Board. “The importance of these programs was acknowledged in Proposition 14 and we expect that they will continue to be important components of CIRM’s programs and strategic direction in the years to come.”

Most undergraduate research training programs, including those targeting students from underserved communities, target individuals with predefined academic credentials as well as a stated commitment towards graduate school, medical school, or faculty positions in academia. COMPASS will support the development and implementation of novel strategies to recognize and foster untapped talent that can lead to new and valuable perspectives that are specific to the challenges of regenerative medicine, and that will create new paths to a spectrum of careers that are not always apparent to students in the academic, undergraduate environment.

COMPASS will complement but not compete with CIRM’s Bridges program, a subset of which serve a different, but equally important population of undergraduate trainees; similarly, the program is unlikely to compete for the same pools of students that would be most likely to receive support through the major NIH Training Programs such as MARC and RISE.

Here are the 16 successful applicants.

Application numberTitlePrincipal InvestigatorAmount
EDUC5-13840  The COMPASS Scholars Program – Developing Today’s Untapped Talent into Tomorrow’s STEM Cell Researchers    John Matsui, University of California, Berkeley    $2,908,950
EDUC5-13634  COMPASS Undergraduate Program  Alice F Tarantal, University of California, Davis    $2,909,950  
EDUC5-13637  Research Mentorship Program in Regenerative Medicine Careers for a Diverse Undergraduate Student Body    Brian J. Cummings, University of California, Irvine    $2,729,900
EDUC5-13665  CIRM COMPASS Training Program (N-COMPASS)  Cindy S Malone, The University Corporation at California State University, Northridge    $2,909,700  
EDUC5-13817  COMPASS: Accelerating Stem Cell Research by Educating and Empowering New Stem Cell Researchers  Tracy L Johnson, University of California, Los Angeles    $2,910,000  
EDUC5-13744  Training and mentorship program in stem cell biology and engineering: A COMPASS for the future  Dennis Clegg, University of California, Santa Barbara    $2,746,000  
EDUC5-13636  Research Training and Mentorship Program to Inspire Diverse Undergraduates toward Regenerative Medicine
Careers (RAMP)
  Huinan Hannah Liu, The Regents of the University of California on behalf of its Riverside Campus    $2,910,000  
EDUC5-13679  Inclusive Pathways for a Stem Cell Scholar (iPSCs) Undergraduate Training Program    Lily Chen, San Francisco State University    $2,894,500
EDUC5-13733  A COMPASS to guide the growth of a diverse regenerative medicine workforce that represents California and benefits
the world
  Kristen OHalloran Cardinal, Cal Poly Corporation, an Auxiliary of California Polytechnic State University, San Luis Obispo    $2,887,939  
EDUC5-13619  Increase Diversity, Equity, and Advancement in Cell Based Manufacturing Sciences (IDEA-CBMS)  Michael Fino, MiraCosta College    $2,894,500  
EDUC5-13667  COMPASS Program for Southern California Hispanic Serving Institution  Bianca Romina Mothé, California State University San Marcos Corporation    $2,877,200  
EDUC5-13653  Student Pluripotency: Realizing Untapped Undergraduate Potential in Regenerative Medicine  Daniel Nickerson, California State University, San Bernardino    $2,909,853  
EDUC5-13647  COMPASS: an inclusive Pipeline for Research and Other Stem cell-based Professions in Regenerative medicine
(iPROSPR)  
  Alison Miyamoto, CSU Fullerton Auxiliary Services Corporation    $2,883,440
EDUC5-13686  Training Undergraduates in Stem Cell Engineering and Biology (TUSCEB)    Kara E McCloskey, University of California, Merced    $2,909,999
EDUC5-13853  COMPASS: Guiding Undergraduates to Careers in Regenerative Medicine    Senta Georgia, University of Southern California    $2,899,999
EDUC5-13910  IDEA-CBMS – Increase Diversity, Equity, and Advancement in Cell Based Manufacturing Sciences    James Dekloe, Solano Community College    $2,894,500

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.

The present and future of regenerative medicine

One of the great pleasures of my job is getting to meet the high school students who take part in our SPARK or Summer Internship to Accelerate Regenerative Medicine Knowledge program. It’s a summer internship for high school students where they get to spend a couple of months working in a world class stem cell and gene therapy research facility. The students, many of whom go into the program knowing very little about stem cells, blossom and produce work that is quite extraordinary.

One such student is Tan Ieng Huang, who came to the US from China for high school. During her internship at U.C. San Francisco she got to work in the lab of Dr. Arnold Kriegstein. He is the Founding Director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco. Not only did she work in his lab, she took the time to do an interview with him about his work and his thoughts on the field.

It’s a fascinating interview and shows the creativity of our SPARK students. You will be seeing many other examples of that creativity in the coming weeks. But for now, enjoy the interview with someone who is a huge presence in the field today, by someone who may well be a huge presence in the not too distant future.

‘a tête-à-tête with Prof. Arnold Kriegstein’

The Kriegstein lab team: Photo courtesy UCSF

Prof. Arnold Kriegstein is the Founding Director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco. Prof. Kriegstein is also the Co-Founder and Scientific Advisor of Neurona Therapeutics which seeks to provide effective and safe cell therapies for chronic brain disorder. A Clinician by training, Prof. Kriegstein has been fascinated by the intricate workings of the human brain. His laboratory focuses on understanding the transcriptional and signaling networks active during brain development, the diversity of neuronal cell types, and their fate potential. For a long time, he has been interested in harnessing this potential for translational and therapeutic intervention.

During my SEP internship I had the opportunity to work in the Kriegstein lab. I was in complete awe. I am fascinated by the brain. During the course of two months, I interacted with Prof. Kriegstein regularly, in lab meetings and found his ideas deeply insightful. Here’s presenting some excerpts from some of our discussions, so that it reaches many more people seeking inspiration!

Tan Ieng Huang (TH): Can you share a little bit about your career journey as a scientist?

Prof. Arnold Kriegstein (AK): I wanted to be a doctor when I was very young, but in high school I started having some hands-on research experience. I just loved working in the lab. From then on, I was thinking of combining those interests and an MD/PhD turned out to be an ideal course for me. That was how I started, and then I became interested in the nervous system. Also, when I was in high school, I spent some time one summer at Rockefeller University working on a project that involved operant conditioning in rodents and I was fascinated by behavior and the role of the brain in learning and memory. That happened early on, and turned into an interest in cortical development and with time, that became my career.

TH: What was your inspiration growing up, what made you take up medicine as a career?

AK: That is a little hard to say, I have an identical twin brother. He and I used to always share activities, do things together. And early on we actually became eagle scouts, sort of a boy scout activity in a way. In order to become an eagle scout without having to go through prior steps, we applied to a special program that the scouts had, which allowed us to shadow physicians in a local hospital. I remember doing that at a very young age. It was a bit ironic, because one of the evenings, they showed us films of eye surgery, and my brother actually fainted when they made an incision in the eye. The reason it makes me laugh now is because my brother became an eye surgeon many years later. But I remember our early experience, we both became very fascinated by medicine and medical research.

Tan Ieng and Dr. Arnold Kriegstein at UCSF

TH: What inspired you to start the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research Institute?

AK: My interest in brain development over the years became focused on earlier stages of development and eventually Neurogenesis, you know, how neurons are actually generated during early stages of in utero brain development. In the course of doing that we discovered that the radial glial cells, which have been thought for decades to simply guide neurons as they migrate, turned out to actually be the neural stem cells, they were making the neurons and also guiding them toward the cortex. So, they were really these master cells that had huge importance and are now referred to as neural stem cells. But at that time, it was really before the stem cell field took off. But because we studied neurogenesis, because I made some contributions to understanding how the brain develops from those precursors or progenitor cells, when the field of stem cells developed, it was very simple for me to identify as someone who studied neural stem cells. I became a neural stem cell scientist. I started a neural stem cell program at Columbia University when I was a Professor there and raised 15 million dollars to seed the program and hired new scientists. It was shortly after that I was approached to join UCSF as the founder of a new stem cell program. And it was much broader than the nervous system; it was a program that covered all the different tissues and organ systems.

TH: Can you tell us a little bit about how stem cell research is contributing to the treatment of diseases? How far along are we in terms of treatments?

AK: It’s taken decades, but things are really starting to reach the clinic now. The original work was basic discovery done in research laboratories, now things are moving towards the clinic. It’s a really very exciting time. Initially the promise of stem cell science was called Regenerative medicine, the idea of replacing injured or worn-out tissues or structures with new cells and new tissues, new organs, the form of regeneration was made possible by understanding that there are stem cells that can be tweaked to actually help make new cells and tissues. Very exciting process, but in fact the main progress so far hasn’t been replacing worn out tissues and injured cells, but rather understanding diseases using human based model of disease. That’s largely because of the advent of induced pluripotent stem cells, a way of using stem cells to make neurons or heart cells or liver cells in the laboratory, and study them both in normal conditions during development and in disease states. Those platforms which are relatively easy to make now and are pretty common all over the world allow us to study human cells rather than animal cells, and the hope is that by doing that we will be able to produce conventional drugs and treatments that work much better than ones we had in the past, because they will be tested in actual human cells rather than animal cells.

TH: That is a great progress and we have started using human models because even though there are similarities with animal models, there are still many species-specific differences, right?

AK: Absolutely, in fact, one of the big problems now in Big Pharma, you know the drug companies, is that they invest millions and sometimes hundreds of millions of dollars in research programs that are based on successes in treating mice, but patients don’t respond the same way. So the hope is that by starting with a treatment that works on human cells it might be more likely that the treatment will work on human patients.

TH: What are your thoughts on the current challenges and future of stem cell research?

AK: I think this is an absolute revolution in modern medicine, the advent of two things that are happening right now, first the use of induced pluripotent stem cells, the ability to make pluripotent cells from adult tissue or cells from an individual allows us to use models of diseases that I mentioned earlier from actual patients. That’s one major advance. And the other is gene editing, and the combination of gene editing and cell-based discovery science allows us to think of engineering cells in ways that can make them much more effective as a form of cell therapy and those cell therapies have enormous promise. Right now, they are being used to treat cancer, but in the future, they might be able to treat heart attack, dementia, neurodegenerative diseases, ALS, Parkinson’s disease, a huge list of disorders that are untreatable right now or incurable. They might be approached by the combination of cell-based models, cell therapies, and gene editing.

TH: I know there are still some challenges right now, like gene editing has some ethical issues because people don’t know if there can be side effects after the gene editing, what are your thoughts?

AK: You know, like many other technologies there are uncertainties, and there are some issues. Some of the problems are off-target effects, that is you try to make a change in one particular gene, and while doing that you might change other genes in unexpected ways and cause complications. But we are understanding that more and more now and can make much more precise gene editing changes in just individual genes without affecting unanticipated areas of the genome. And then there are also the problems of how to gene-edit cells in a safe way. There are certain viral factors that can be used to introduce the gene editing apparatus into a cell, and sometimes if you are doing that in a patient, you can also have unwanted side effects from the vectors that you are using, often they are modified viral vectors. So, things get complicated very quickly when you start trying to treat patients, but I think these are all tractable problems and I think in time they will all be solved. It will be a terrific, very promising future when it comes to treating patients who are currently untreatable.

TH: Do you have any advice for students who want to get into this field?

AK: Yes, I think it’s actually never been a better time and I am amazed by the technologies that are available now. Gene editing that I mentioned before but also single cell approaches, the use of single cell multiomics revealing gene expression in individual cells, the molecular understanding of how individual cells are formed, how they are shaped, how they change from one stage to another, how they can be forced into different fates. It allows you to envision true Regenerative medicine, improving health by healing or replacing injured or diseased tissues. I think this is becoming possible now, so it’s a very exciting time. Anyone who has an interest in stem cell biology or new ways of treating diseases, should think about getting into a laboratory or a clinical setting. I think this time is more exciting than it’s ever been.

TH: So excited to hear that, because in school we have limited access to the current knowledge, the state-of-art. I want to know what motivates you every day to do Research and contribute to this field?

AK: Well, you know that I have been an MD/PhD, as I mentioned before, in a way, there are two different reward systems at play. In terms of the PhD and the science, it’s the discovery part that is so exciting. Going in every day and thinking that you might learn something that no one has ever known before and have a new insight into a mechanism of how something happens, why it happens. Those kinds of new insights are terrifically satisfying, very exciting. On the MD side, the ability to help patients and improve peoples’ lives is a terrific motivator. I always wanted to do that, was very driven to become a Neurologist and treat both adult and pediatric patients with neurological problems. In the last decade or so, I’ve not been treating patients so much, and have focused on the lab, but we have been moving some of our discoveries from the laboratory into the clinic. We have just started a clinical trial, of a new cell-based therapy for epilepsy in Neurona Therapeutics, which is really exciting. I am hoping it will help the patients but it’s also a chance to actually see something that started out as a project in the laboratory become translated into a therapy for patients, so that’s an achievement that has really combined my two interests, basic science, and clinical medicine. It’s a little late in life but not too late, so I’m very excited about that.

Tan Ieng Huang, Kriegstein Lab, SEP Intern, CIRM Spark Program 2022

First patient dosed in clinical trial for a drug-resistant form of epilepsy

Tablet BM47753. Neo-Babylonian Period. Courtesy of the British Museum, London.

Epilepsy seems to have been a problem for people for as long as people have been around. The first recorded mention of it is on a 4000-year-old Akkadian tablet found in Mesopotamia (modern day Iraq). The tablet includes a description of a person with “his neck turning left, hands and feet are tense, and his eyes wide open, and from his mouth froth is flowing without him having any consciousness.”

Despite that long history, effective treatments for epilepsy were a long time coming. It wasn’t till the middle of the 19th century that physicians started using bromides to help people with the condition, but they also came with some nasty side effects, including depression, weakness, fatigue, lethargy, and coma.

Fast forward 150 years or so and we are now, hopefully, entering a new era. This week, Neurona Therapeutics announced they had dosed the first patient in their first-in-human clinical trial formesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults. The trial specifically targets people who have a drug-resistant form of MTLE.

Neurona has developed a therapy called NRTX-1001, consisting of a specialized type of neuronal or brain cell derived from embryonic stem cells.  These cells are injected into the brain in the area affected by the seizures where they release a neurotransmitter or chemical messenger that will block the signals in the brain causing the epileptic seizures. Pre-clinical testing suggests a single dose of NRTX-1001 may have a long-lasting ability to suppress seizures.

A new approach is very much needed because current therapies for drug-resistant epilepsy are only partially effective and have serious drawbacks. One treatment that can significantly reduce seizure frequency is the removal of the affected part of the brain, however this can cause serious, irreversible damage, such as impacting memory, mood and vision.

CIRM has a vested interest in seeing this therapy succeed. We have invested more than $14 million over four different awards, in helping this research progress from a basic or Discovery level through to the current clinical trial.

In a news release, two key figures in administering the first dose to a patient said this was an important step forward. 

Harish Babu, M.D., Ph.D., assistant professor of neurosurgery at SUNY Upstate Medical University said: “Neurona’s regenerative cell therapy approach has the potential to provide a single-administration, non-destructive alternative for the treatment of drug-resistant focal epilepsy. Currently, people with mesial temporal lobe epilepsy who are not responsive to anti-seizure medications have few options, such as an invasive surgery that removes or destroys the affected brain tissue.”

Robert Beach, M.D., Ph.D. professor of neurology at SUNY Upstate Medical University added: “The objective of NRTX-1001 is to add cells that have the potential to repair the circuits that are damaged in epilepsy and thus reduce seizure activity.”

There is a huge unmet medical need for an effective, long-term therapy. Right now, it’s estimated that three million Americans have epilepsy, and 25 to 35 percent live with ongoing seizures despite dozens of approved drugs on the market.

If this therapy works it might mean that 4,000 year old tablet will become a medical footnote, rather than a reminder that we still have work to do.

Stem Cell Agency Board Invests in 19 Discovery Research Programs Targeting Cancers, Heart Disease and Other Disorders

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Dr. Judy Shizuru, Stanford University

While stem cell and gene therapy research has advanced dramatically in recent years, there are still many unknowns and many questions remaining about how best to use these approaches in developing therapies. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) today approved investing almost $25 million in 19 projects in early stage or Discovery research.

The awards are from CIRM’s DISC2 Quest program, which supports  the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.

“Every therapy that helps save lives or change lives begins with a researcher asking a simple question, “What if?”, says Dr. Maria T. Millan, the President and CEO of CIRM. “Our Quest awards reflect the need to keep supporting early stage research, to gain a deeper understanding of stem cells work and how we can best tap into that potential to advance the field.”

Dr. Judy Shizuru at Stanford University was awarded $1.34 million to develop a safer, less-toxic form of bone marrow or hematopoietic stem cell transplant (HCT). HCT is the only proven cure for many forms of blood disorders that affect people of all ages, sexes, and races worldwide. However, current 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.

Dr. Shizuru proposes developing an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells. This would make stem cell transplant safer and more effective for the treatment of many life-threatening blood disorders, and more accessible for people in rural or remote parts of the country.

Lili Yang UCLA Broad Stem Cell Research Center: Photo courtesy Reed Hutchinson PhotoGraphics

Dr. Lili Yang at UCLA was awarded $1.4 million to develop an off-the-shelf cell therapy for ovarian cancer, which causes more deaths than any other cancer of the female reproductive system.

Dr. Yang is using immune system cells, called invariant natural killer T cells (iNKT) to attack cancer cells. However, these iNKT cells are only found in small numbers in the blood so current approaches involve taking those cells from the patient and, in the lab, modifying them to increase their numbers and strength before transplanting them back into the patient. This is both time consuming and expensive, and the patient’s own iNKT cells may have been damaged by the cancer, reducing the likelihood of success.

In this new study Dr. Yang will use healthy donor cord blood cells and, through genetic engineering, turn them into the specific form of iNKT cell therapy targeting ovarian cancer. This DISC2 award will support the development of these cells and do the necessary testing and studies to advance it to the translational stage.

Timothy Hoey and Tenaya Therapeutics Inc. have been awarded $1.2 million to test a gene therapy approach to replace heart cells damaged by a heart attack.

Heart disease is the leading cause of death in the U.S. with the highest incidence among African Americans. It’s caused by damage or death of functional heart muscle cells, usually due to heart attack. Because these heart muscle cells are unable to regenerate the damage is permanent. Dr. Hoey’s team is developing a gene therapy that can be injected into patients and turn their cardiac fibroblasts, cells that can contribute to scar tissue, into functioning heart muscle cells, replacing those damaged by the heart attack.

The full list of DISC2 Quest awards is:

APPLICATION NUMBERTITLE OF PROGRAMPRINCIPAL INVESTIGATORAMOUNT
  DISC2-13400  Targeted Immunotherapy-Based Blood Stem Cell Transplantation    Judy Shizuru, Stanford Universtiy  $1,341,910    
  DISC2-13505  Combating Ovarian Cancer Using Stem Cell-Engineered Off-The-Shelf CAR-iNKT Cells    Lili Yang, UCLA  $1,404,000
  DISC2-13515  A treatment for Rett syndrome using glial-restricted
neural progenitor cells  
  Alysson Muotri, UC San Diego  $1,402,240    
  DISC2-13454  Targeting pancreatic cancer stem cells with DDR1 antibodies.    Michael Karin, UC San Diego  $1,425,600  
  DISC2-13483  Enabling non-genetic activity-driven maturation of iPSC-derived neurons    Alex Savtchenko, Nanotools Bioscience  $675,000
  DISC2-13405  Hematopoietic Stem Cell Gene Therapy for Alpha
Thalassemia  
  Don Kohn, UCLA    $1,323,007  
    DISC2-13507  CAR T cells targeting abnormal N-glycans for the
treatment of refractory/metastatic solid cancers  
  Michael Demetriou, UC Irvine  $1,414,800  
  DISC2-13463  Drug Development of Inhibitors of Inflammation Using
Human iPSC-Derived Microglia (hiMG)  
  Stuart Lipton, Scripps Research Inst.  $1,658,123  
  DISC2-13390  Cardiac Reprogramming Gene Therapy for Post-Myocardial Infarction Heart Failure    Timothy Hoey, Tenaya Therapeutics  $1,215,000  
  DISC2-13417  AAV-dCas9 Epigenetic Editing for CDKL5 Deficiency Disorder    Kyle Fink, UC Davis  $1,429,378  
  DISC2-13415  Defining the Optimal Gene Therapy Approach of
Human Hematopoietic Stem Cells for the Treatment of
Dedicator of Cytokinesis 8 (DOCK8) Deficiency  
  Caroline Kuo, UCLA  $1,386,232  
  DISC2-13498  Bioengineering human stem cell-derived beta cell
organoids to monitor cell health in real time and improve therapeutic outcomes in patients  
  Katy Digovich, Minutia, Inc.  $1,198,550  
  DISC2-13469  Novel antisense therapy to treat genetic forms of
neurodevelopmental disease.  
  Joseph Gleeson, UC San Diego  $1,180,654  
  DISC2-13428  Therapeutics to overcome the differentiation roadblock in Myelodysplastic Syndrome (MDS)    Michael Bollong, Scripps Research Inst.  $1,244,160  
  DISC2-13456  Novel methods to eliminate cancer stem cells    Dinesh Rao, UCLA  $1,384,347  
  DISC2-13441  A new precision medicine based iPSC-derived model to study personalized intestinal fibrosis treatments in
pediatric patients with Crohn’s diseas  
  Robert Barrett Cedars-Sinai  $776,340
  DISC2-13512  Modified RNA-Based Gene Therapy for Cardiac
Regeneration Through Cardiomyocyte Proliferation
  Deepak Srivastava, Gladstone Institutes  $1,565,784
  DISC2-13510  An hematopoietic stem-cell-based approach to treat HIV employing CAR-T cells and anti-HIV broadly
neutralizing antibodies  
  Brian Lawson, The Scintillon Institute  $1,143,600  
  DISC2-13475  Developing gene therapy for dominant optic atrophy using human pluripotent stem cell-derived retinal organoid disease model    Xian-Jie Yang, UCLA  $1,345,691  

The long road to developing a therapy for epilepsy

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Good science takes time. That’s an important guiding phrase for researchers looking to develop new therapies. But it’s also a frustrating reality for patients who are waiting for something to help them now.

That point was driven home last week when the governing board of the California Institute for Regenerative Medicine (CIRM) voted to invest almost $8 million to test a new approach to treating a drug-resistant form of epilepsy. This approach holds a lot of promise but getting to this point has not been easy or quick.

Epilepsy is one of the most common neurological disorders in the US, affecting more than three million people. More than one third of those people have a form of epilepsy that doesn’t respond to current medications, so the only options are surgery or using lasers (LITT) to remove the affected part of the brain. Not surprisingly this can cause serious, irreversible damage, such as effects on memory, mood and vision. Equally unsurprising, because of those impacts many people are reluctant to go that route.

Now a company called Neurona Therapeutics has developed a new approach called NRTX-1001. This consists of a specialized type of neuronal or brain cell that is derived from embryonic stem cells (hESCs).  These neuronal cells are injected into the brain in the area affected by the seizures where they release a neurotransmitter or chemical messenger that will block the signals in the brain causing the epileptic seizures. Pre-clinical testing suggests a single dose of NRTX-1001 may have a long-lasting ability to suppress seizures.

Cory Nicholas, PhD, the Co-Founder and CEO of Neurona says this approach will be tested on people with drug-resistant temporal lobe epilepsy, the most common form of epilepsy.

“To our knowledge, NRTX-1001 is the first human cell therapy to enter clinical trials for epilepsy. This cell therapy has the potential to provide a less invasive, non-tissue destructive, regenerative alternative for people with chronic focal seizures.” 

“Epilepsy patient advocates and clinicians have said that such a regenerative cell therapy could represent a first option that, if successful, could obviate the need for lobectomy/LITT. And for those not eligible for lobectomy/LITT, cell therapy could provide the only option to potentially achieve seizure-freedom.”

Nicholas says this work didn’t happen overnight. “This effort to develop regenerative cell therapy for epilepsy officially began in the early 2000’s from the laboratories of John Rubenstein, MD, PhD, Arturo Alvarez-Buylla, PhD, and Arnold Kriegstein, MD, PhD, at UC San Francisco. They were among the first to understand how specialized inhibitory nerve cells, called interneurons, develop from neural stem cells in our forebrain before birth. Subsequently, they pioneered the extraction and use of these cells as a cell therapy in preclinical models.”

Over the years the group working on this approach expanded, later becoming Neurona Therapeutics, and CIRM supported that work with several awards.

“CIRM provided the necessary funds and expertise to help translate our discoveries toward the clinic using human embryonic stem cell (hESC) technology to generate a sustainable supply of interneuron cells for further evaluation. Truly, CIRM has been the essential catalyst in accelerating this important research from bench to bedside.”

Nicholas says its immensely gratifying to be part of this work, and to know that if it succeeds it will be life-altering, even life-saving, for so many people.

“It is difficult to reflect back with all the work that is happening at present on the first-in-human trial, but it is always emotional for me to think about our amazing team: Neurona employees, CIRM staff, clinicians, professors, trainees, collaborators, and investors; who have worked tirelessly in contributing to the advancement of this therapeutic mission. I am deeply humbled by the opportunity to be part of this innovative, rigorous, and compassionate effort, and by the responsibility to the brave patients participating in the study. We remain steadfast in our commitment to patient safety and cautiously optimistic that NRTX-1001 cell therapy will improve quality of life for people living with chronic focal epilepsy. Moreover, we are sincerely thankful to Californians for their commitment to CIRM’s vision, and we are proud to be a part of this groundbreaking initiative that has put our state at the forefront, dedicated to fulfilling the promise of regenerative medicine.”