Nearly 3.5 million Americans suffer from some form of epilepsy. It can affect people in different ways from stiff muscles or staring spells, to violent shaking and loss of consciousness.
The impact it has on people’s lives extends far beyond the condition itself. People who suffer from epilepsy experience a higher frequency of depression and other mood disorders, social isolation, challenges in school and with living independently, higher unemployment, limitations on driving, and higher risk of early death.
Medications can help control the seizures in some people, but around one-third of patients don’t respond to those drugs. The alternative is surgery, which is invasive and can cause damage to delicate brain tissue.
Neurona Therapeutics —a clinical stage biotherapeutics company— has developed a therapy called NRTX-1001, which consists 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.
So far, the first two patients treated in the groundbreaking clinical trial—both of whom entered the study with a history of significant monthly seizures that were not controlled by anti-seizure medications—have seen encouraging signs of reduction which suggest that a single dose of NRTX-1001 may have a long-lasting ability to suppress seizures.
The first patient had a 9-year history of seizures and in the six months prior to the administration of NRTX-1001, the patient experienced an average of 32 seizures per month, despite being on several antiepileptic medications. The patient received a single administration of NRTX-1001, the treatment was well tolerated, and there have been no serious or severe adverse events associated with the treatment to date. The patient reported four seizures during the first three months since receiving NRTX-1001.
The second patient treated in the trial also had drug-resistant seizures, with an average of 14 seizures per month in the six months prior to treatment. This individual received NRTX-1001 and in the first week post-treatment had not experienced any serious or severe adverse events, or seizures.
“The early clinical results with NRTX-1001 in epilepsy are very encouraging, and we look forward to enrolling additional patients in the study,” said Dr. Cory Nicholas, Neurona’s president and chief executive officer. “NRTX-1001 is designed to be an off-the-shelf, one-time administration therapy with the potential to durably eliminate seizures and provide a new regenerative cell therapeutic approach in patients for whom anti-seizure medication has failed.”
Dr. Nicholas added, “It has the potential to be disease-modifying without the tissue-destructive procedural risks associated with lobectomy. Further, there are many who are not currently eligible for lobectomy surgery who may be eligible for NRTX-1001 in the future. We are sincerely grateful to everyone involved in the development of NRTX-1001, including the first participants in this pioneering study, their families, and the respective clinical site teams.”
The California Institute for Regenerative Medicine has a vested interest in seeing this therapy succeed. CIRM has 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.
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.
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 Program2022
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.
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.”
A new therapeutic approach, supported by CIRM, that blocks the signals in the brain that can cause epilepsy has been given permission by the US Food and Drug Administration (FDA) to be tested in a clinical trial.
Nearly 3.5 million Americans suffer from some form of epilepsy. It can affect people in different ways from stiff muscles or staring spells, to violent shaking and loss of consciousness. The impact it has on people’s lives extends far beyond the condition itself. People who suffer from epilepsy experience a higher frequency of depression and other mood disorders, social isolation, challenges in school and with living independently, higher unemployment, limitations on driving, and higher risk of early death.
Medications can help control the seizures in some people, but around one-third of patients don’t respond to those drugs. The alternative is surgery, which is invasive and can cause damage to delicate brain tissue.
Now Neurona Therapeutics has developed an approach, called NRTX-1001, that turns stem cells into interneurons, a kind of nerve cell in the brain. These cells secrete chemical messengers, called GABA inhibitory neurotransmitters, that help rebalance the misfiring electrical signals in the brain and hopefully eliminate or reduce the seizures.
Cory Nicholas, PhD, Neuron’s Therapeutics co-founder and CEO, said getting the go-ahead from the FDA for a clinical trial is a key milestone for the company. “Neurona’s accomplishments are a testament to longstanding support from CIRM. CIRM has supported the NRTX-1001 program from bench to bedside, dating back to early research in the Neurona founders’ laboratories at the University of California, San Francisco to the recent IND-enabling studies conducted at Neurona. It’s an exciting time for the field of regenerative medicine and is gratifying to see the NRTX-1001 neuronal cell therapy now cleared by the FDA to enter clinical testing in people who have drug resistant temporal lobe epilepsy. We are thankful to CIRM for their support of this important work that has the potential to provide seizure-freedom for patients who currently have limited treatment options.”
In a news release Dr. Nicholas said the timing was perfect. “This milestone is especially rewarding and timely given that November is Epilepsy Awareness Month. NRTX-1001 is a new type of inhibitory cell therapy that is targeted to the focal seizure onset region in the brain and, in a single treatment, has the potential to significantly improve the lives of people living with focal epilepsy.”
In animal models NRTX-1001 produced freedom from seizures in more than two-thirds of the treated group, compared to just 5 percent of the untreated group. It also resulted in reduced tissue damage in the seizure-affected area of the brain.
The clinical trial will initially target people affected by mesial temporal lobe epilepsy (MTLE) where seizures often begin in a structure called the hippocampus. MTLE is the most common type of focal epilepsy.
CIRM has invested almost $6.67 million in funding three stages of this project, from the early Discovery work to this latest late-stage preclinical work, highlighting our commitment to doing all we can to advance the most promising science from the bench to the bedside.
Last week, the CIRM Board approved $32.92 million in awards directed towards four new clinical trials in vision related diseases and Parkinson’s Disease.
In addition to these awards, the Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.
Before we go into more specific details of each one of these awards, here is a table summarizing these four new projects:
Application
Title
Institution
Award Amount
TRAN1 11536
Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome
UCLA
$4,896,628
TRAN1 11555
BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma
UCLA
$3,176,805
TRAN1 11544
Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer
City of Hope
$2,873,262
TRAN1 11611
Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsy
Neurona Therapeutics
$4,848,750
Dr. Caroline Kuo, UCLA
$4.89 million was awarded to Dr. Caroline Kuo at UCLA to pursue a gene therapy approach for X-Linked Hyper IgM Syndrome (X-HIM).
X-HIM is a hereditary immune disorder
observed predominantly in males in which there are abnormal levels of different
types of antibodies in the body.
Antibodies are also known as Immunoglobulin (Ig) and they combat
infections by attaching to germs and other foreign substances, marking them for
destruction. In infants with X-HIM,
there are normal or high levels of antibody IgM but low levels of antibodies
IgG, IgA, and IgE. The low level of
these antibodies make it difficult to fight off infection, resulting in
frequent pneumonia, sinus infections, ear infections, and parasitic
infections. Additionally, these infants
have an increased risk of cancerous growths.
The gene therapy approach Dr. Kuo is
continuing to develop involves using CRISPR/Cas9 technology to modify human
blood stem cells with a functional version of the gene necessary for normal
levels of antibody production. The
ultimate goal would be to take a patient’s own blood stem cells, modify them
with the corrected gene, and reintroduce them back into the patient.
CIRM has previously funded Dr. Kuo’s earlier work related to developing this gene therapy approach for XHIM.
Dr. Yvonne Chen, UCLA
$3.17 million was awarded to Dr. Yvonne Chen at UCLA to develop a CAR-T cell therapy for multiple myeloma (MM).
MM is a type of blood cancer that forms in
the plasma cell, a type of white blood cell that is found in the bone marrow. An estimated 32,110 people in the United
States will be diagnosed with MM in 2019 alone.
Several treatment options are available to patients with MM, but there
is no curative therapy.
The therapy that Dr. Chen is developing will consist of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T cells will be modified with a protein called a chimeric antigen receptor (CAR) that will recognize BCMA and CS1, two different markers found on the surface of MM cells. These modified T cells (CAR-T cells) are then infused into the patient, where they are expected to detect and destroy BCMA and CS1 expressing MM cells.
Dr. Chen is using CAR-T cells that can detect two different markers in a separate clinical trial that you can read about in a previous blog post.
Dr. Karen Aboody, City of Hope
$2.87 million was awarded to Dr. Karen Aboody at City of Hope to develop an immunotherapy delivered via neural stem cells (NSCs) for treatment of ovarian cancer.
Ovarian cancer affects approximately 22,000
women per year in the United States alone.
Most ovarian cancer patients eventually develop resistance to
chemotherapy, leading to cancer progression and death, highlighting the need
for treatment of recurring ovarian cancer.
The therapy that Dr. Aboody is developing will use an established line of NSCs to deliver a virus that specifically targets these tumor cells. Once the virus has entered the tumor cell, it will continuously replicate until the cell is destroyed. The additional copies of the virus will then go on to target neighboring tumor cells. This process could potentially stimulate the body’s own immune response to fight off the cancer cells as well.
Dr. Cory Nicholas, Neurona Therapeutics
$4.85
million was awarded to Dr. Cory Nicholas at Neurona Therapeutics to
develop a treatment for epilepsy.
Epilepsy affects more than 3 million people in the United States with about 150,000 newly diagnosed cases in the US every year. It results in persistent, difficult to manage, or uncontrollable seizures that can be disabling and significantly impair quality of life. Unfortunately, anti-epileptic drugs fail to manage the disease in a large portion of people with epilepsy. Approximately one-third of epilepsy patients are considered to be drug-resistant, meaning that they do not adequately respond to at least two anti-epileptic drugs.
The
therapy that Dr. Nicholas is developing will derive interneurons from human
embryonic stem cells (hESCs). These newly derived interneurons would then be
delivered to the brain via injection whereby the new cells are able to help
regulate aberrant brain activity and potentially eliminate or significantly
reduce the occurrence of seizures.
The governing Board of the California Institute for Regenerative Medicine (CIRM) yesterday invested $32.92 million to fund the Stem Cell Agency’s first clinical trial in Parkinson’s disease (PD), and to support three clinical trials targeting different forms of vision loss.
This brings the total number of clinical trials funded by CIRM to 60.
The PD trial will be carried out by Dr. Krystof Bankiewicz at Brain Neurotherapy Bio, Inc. He 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.
David Higgins, PhD, a CIRM Board member and patient advocate for Parkinson’s says there is a real need for new approaches to treating the disease. In the US alone, approximately 60,000 people are diagnosed with PD each year and it is expected that almost one million people will be living with the disease by 2020.
“Parkinson’s Disease is a serious unmet medical need and, for reasons we don’t fully understand, its prevalence is increasing. There’s always more outstanding research to fund than there is money to fund it. The GDNF approach represents one ‘class’ of potential therapies for Parkinson’s Disease and has the potential to address issues that are even broader than this specific therapy alone.”
The Board also approved funding for two clinical trials targeting retinitis pigmentosa (RP), a blinding eye disease that affects approximately 150,000 individuals in the US and 1.5 million people around the world. It is caused by the destruction of light-sensing cells in the back of the eye known as photoreceptors. This leads to gradual vision loss and eventually blindness. There are currently no effective treatments for RP.
Dr. Henry Klassen and his team at jCyte are injecting human retinal progenitor cells (hRPCs), into the vitreous cavity, a gel-filled space located in between the front and back part of the eye. The proposed mechanism of action is that hRPCs secrete neurotrophic factors that preserve, protect and even reactivate the photoreceptors, reversing the course of the disease.
CIRM has supported early development of Dr. Klassen’s approach as well as preclinical studies and two previous clinical trials. The US Food and Drug Administration (FDA) has granted jCyte Regenerative Medicine Advanced Therapy (RMAT) designation based on the early clinical data for this severe unmet medical need, thus making the program eligible for expedited review and approval.
The other project targeting RP is led by Dr. Clive Svendsen from the Cedars-Sinai Regenerative Medicine Institute. In this approach, human neural progenitor cells (hNPCs) are transplanted to the back of the eye of RP patients. The goal is that the transplanted hNPCs will integrate and create a protective layer of cells that prevent destruction of the adjacent photoreceptors.
The third trial focused on vision destroying diseases is led by Dr. Sophie Deng at the University of California Los Angeles (UCLA). Dr. Deng’s clinical trial addresses blinding corneal disease by targeting limbal stem cell deficiency (LSCD). Under healthy conditions, limbal stem cells (LSCs) continuously regenerate the cornea, the clear front surface of the eye that refracts light entering the eye and is responsible for the majority of the optical power. Without adequate limbal cells , inflammation, scarring, eye pain, loss of corneal clarity and gradual vision loss can occur. Dr. Deng’s team will expand the patient’s own remaining LSCs for transplantation and will use novel diagnostic methods to assess the severity of LSCD and patient responses to treatment. This clinical trial builds upon previous CIRM-funded work, which includes early translational and late stage preclinical projects.
“CIRM funds and accelerates promising early stage research, through development and to clinical trials,” says Maria T. Millan, MD, President and CEO of CIRM. “Programs, such as those funded today, that were novel stem cell or gene therapy approaches addressing a small number of patients, often have difficulty attracting early investment and funding. CIRM’s role is to de-risk these novel regenerative medicine approaches that are based on rigorous science and have the potential to address unmet medical needs. By de-risking programs, CIRM has enabled our portfolio programs to gain significant downstream industry funding and partnership.”
CIRM Board also awarded $5.53 million to Dr. Rosa Bacchetta at Stanford to complete work necessary to conduct a clinical trial for IPEX syndrome, a rare disease caused by mutations in the FOXP3 gene. Immune cells called regulatory T Cells normally function to protect tissues from damage but in patients with IPEX syndrome, lack of functional Tregs render the body’s own tissues and organs to autoimmune attack that could be fatal in early childhood. Current treatment options include a bone marrow transplant which is limited by available donors and graft versus host disease and immune suppressive drugs that are only partially effective. Dr. Rosa Bacchetta and her team at Stanford will use gene therapy to insert a normal version of the FOXP3 gene into the patient’s own T Cells to restore the normal function of regulatory T Cells.
The CIRM Board also approved investing $15.80 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.
The TRAN1 Awards are summarized in the table below:
Application
Title
Institution
Award Amount
TRAN1 11536
Ex Vivo Gene Editing of Human Hematopoietic Stem Cells for the Treatment of X-Linked Hyper IgM Syndrome
UCLA
$4,896,628
TRAN1 11555
BCMA/CS1 Bispecific CAR-T Cell Therapy to Prevent Antigen Escape in Multiple Myeloma
UCLA
$3,176,805
TRAN1 11544
Neural Stem cell-mediated oncolytic immunotherapy for ovarian cancer
City of Hope
$2,873,262
TRAN1 11611
Development of a human stem cell-derived inhibitory neuron therapeutic for the treatment of chronic focal epilepsy
The Stem Cellar 