Three families battling a life-threatening immune disorder got some great news last week. A clinical trial that could save the life of their child has once again been given the go-ahead by the US Food and Drug Administration (FDA).
The clinical trial is the work of UCLA’s Dr. Don Kohn, and was strongly supported by CIRM. It is targeting ADA-SCID, a condition where the child is born without a functioning immune system so even a simple infection could prove fatal. In the past they were called “bubble babies” because some had been placed inside sterile plastic bubbles to protect them from germs.
Dr. Kohn’s approach – using the patient’s own blood stem cells, modified in the lab to correct the genetic mutation that causes the problem – had shown itself to be amazingly effective. In a study in the prestigious New England Journal of Medicine, the researchers showed that of 50 patients treated all had done well and 97 percent were considered cured.
UCLA licensed the therapy to Orchard Therapeutics, who planned to complete the testing needed to apply for permission to make it more widely available. But Orchard ran into problems and shelved the therapy.
After lengthy negotiations Orchard returned the therapy to UCLA last year and now the FDA has given clearance for UCLA to resume treating patients. That is expected to start early next year using CIRM funds left over when Orchard halted its work.
One of the people who played a big role in helping persuade Orchard to return the therapy to UCLA is Alysia Vaccaro. She is the mother of Evie, a child born with ADA-SCID who was cured by Dr. Kohn and his team and is now a thriving 9 year old.
You can watch an interview we did with Alysia about the impact this research has had on her family, and how important it is for other families with ADA-SCID kids.
Every year California performs around 100 kidney transplants in children but, on average, around 50 of these patients will have their body reject the transplant. These children then have to undergo regular dialysis while waiting for a new organ. Even the successful transplants require a lifetime of immunosuppression medications. These medications can prevent rejection but they also increase the risk of infection, gastrointestinal disease, pancreatitis and cancer.
Dr. Alice Bertaina and her team at Stanford University were awarded $11,998,188 to test an approach that uses combined blood stem cell (HSC) and kidney transplantation with the goal to improve outcomes with kidney transplantation in children. This approach seeks to improve on the blood stem cell preparation through an immune-based purification process.
In this approach, the donor HSC are transplanted into the patient in order to prepare for the acceptance of the donor kidney once transplanted. Donor HSC give rise to cells and conditions that re-train the immune system to accept the kidney. This creates a “tolerance” to the transplanted kidney providing the opportunity to avoid long-term need for medications that suppress the immune system.
Pre-clinical data support the idea that this approach could enable the patient to stop taking any immunosuppression medications within 90 days of the surgery.
Dr. Maria T. Millan, President and CEO of CIRM, a former pediatric transplant surgeon and tolerance researcher states that “developing a way to ensure long-term success of organ transplantation by averting immune rejection while avoiding the side-effects of life-long immunosuppression medications would greatly benefit these children.”
The CIRM Board also awarded $7,141,843 to Dr. Ivan Kingand Tachyon Therapeutics, Inc to test a drug showing promise in blocking the proliferation of cancer stem cells in solid tumors such as colorectal and gastrointestinal cancer.
Patients with late-stage colorectal cancer are typically given chemotherapy to help stop or slow down the progression of the disease. However, even with this intervention survival rates are low, usually not more than two years.
Tachyon’s medication, calledTACH101, is intended to target colorectal cancer (CRC) stem cells as well as the bulk tumor by blocking an enzyme called KDM4, which cancer stem cells need to grow and proliferate.
In the first phase of this trial Dr. King and his team will recruit patients with advanced or metastatic solid tumors to assess the safety of TACH101, and determine what is the safest maximum dose. In the second phase of the trial, patients with gastrointestinal tumors and colorectal cancer will be treated using the dose determined in the first phase, to determine how well the tumors respond to treatment.
The CIRM Board also awarded $5,999,919 to Dr. Natalia Gomez-Ospina and her team at Stanford University for a late-stage preclinical program targeting Severe Mucopolysaccharidosis type 1, also known as Hurler syndrome. This is an inherited condition caused by a faulty gene. Children with Hurler syndrome lack an enzyme that the body needs to digest sugar. As a result, undigested sugar molecules build up in the body, causing progressive damage to the brain, heart, and other organs. There is no effective treatment and life expectancy for many of these children is only around ten years.
Dr. Gomez-Ospina will use the patient’s own blood stem cells that have been genetically edited to restore the missing enzyme. The goal of this preclinical program is to show the team can manufacture the needed cells, to complete safety studies and to apply to the US Food and Drug Administration for an Investigational New Drug (IND), the authorization needed to begin a clinical trial in people.
Finally the Board awarded $20,401,260 to five programs as part of its Translational program. The goal of the Translational program is to support promising stem cell-based or gene projects that accelerate completion of translational stage activities necessary for advancement to clinical study or broad end use. Those can include therapeutic candidates, diagnostic methods or devices and novel tools that address critical bottlenecks in research.
The successful applicants are:
APPLICATION
TITLE
PRINCIPAL INVESTIGATOR – INSTITUTION
AMOUNT
TRAN4-14124
Cell Villages and Clinical Trial in a Dish with Pooled iPSC-CMs for Drug Discovery
Nikesh Kotecha — Greenstone Biosciences
$1,350,000
TRAN1-14003
Specific Targeting Hypoxia Metastatic Breast Tumor with Allogeneic Off-the-Shelf Anti-EGFR CAR NK Cells Expressing an ODD domain of HIF-1α
Jianhua Yu — Beckman Research Institute of City of Hope
$6,036,002
TRAN1-13983
CRISPR/Cas9-mediated gene editing of Hematopoietic stem and progenitor cells for Friedreich’s ataxia
Stephanie Cherqui — University of California, San Diego
$4,846,579
TRAN1-13997
Development of a Gene Therapy for the Treatment of Pitt Hopkins Syndrome (PHS) – Translating from Animal Proof of Concept to Support Pre-IND Meeting
Allyson Berent — Mahzi Therapeutics
$4,000,000
TRAN1-13996
Overcoming resistance to standard CD19-targeted CAR T using a novel triple antigen targeted vector
William J Murphy — University of California, Davis
We at the California Institute for Regenerative Medicine have a lot to be thankful for this Thanksgiving. We get to work with some extraordinary colleagues, we get to know some remarkable patient advocates who are pioneers in volunteering for stem cell and gene therapies, and we have a front row seat in a movement that is changing the face of medicine.
We also get to work with some brilliant scientists and help support their research. As if we needed any reminders of how important that funding is, we thought we would share this video with you. It’s from the talented post docs and researchers at the University of California San Diego. It’s a delightful parody of the Cyndi Lauper classic “Girls Just Wanna Have Fun”. Only in this case it’s “Nerds Just Wanna Have Funds.”
Now there’s more encouraging news from a CIRM-funded clinical trial with Jasper Therapeutics. They have announced that they have tested their approach in 16 patients, with encouraging results and no serious adverse events.
Let’s back up a little. Children born with SCID have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life. Several of the approaches CIRM has funded use the child’s own blood stem cells to help fix the problem. But at Jasper Therapeutics they are using another approach. They use a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s own blood supply with one that is free of the SCID mutation, which helps restore their immune system.
However, there’s a problem. Most bone marrow transplants use chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. It can be effective, but it is also toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
To get around that problem Jasper Therapeutics is using an antibody called JSP191 – developed with CIRM funding – that directs the patient’s own immune cells to kill diseased blood stem cells, creating room to transplant new, healthy cells. To date the therapy has already been tested in 16 SCID patients.
In addition to treating 16 patients treated without any apparent problems, Jasper has also been granted Fast Track Designation by the US Food and Drug Administration. This can help speed up the review of treatments that target serious unmet conditions. They’ve also been granted both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.
In a news release, Ronald Martell, President and CEO of Jasper Therapeutics said:
“The FDA’s Fast Track designation granted for JSP191 in Severe Combined Immunodeficiency (SCID) reinforces the large unmet medical need for patients with this serious disease. Along with its previous designations of Orphan and Rare Pediatric Disease for JSP191, the FDA’s Fast Track recognizes JSP191’s potential role in improving clinical outcomes for SCID patients, many of whom are too fragile to tolerate the toxic chemotherapy doses typically used in a transplant.”
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:
Application
Program Title
Institution/Principal Investigator
Amount awarded
INFR4-13579
The Stanford Alpha Stem Cell Clinic
Stanford University – Matthew Porteus
$7,997,246
INFR4-13581
UCSF Alpha Stem Cell Clinic
U.C. San Francisco – Mark Walters
$7,994,347
INFR4-13586
A 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
INFR4-13587
The 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
INFR4-13596
Alpha Stem Cell Clinic for Northern and Central California
U.C. Davis – Mehrdad Abedi
$7,999,997
INFR4-13685
Expansion of the Alpha Stem Cell and Gene Therapy Clinic at UCLA
U.C. Los Angeles – Noah Federman
$8,000,000
INFR4-13878
Alpha Clinic Network Expansion for Cell and Gene Therapies
University of Southern California – Thomas Buchanan
$7,999,983
INFR4-13952
A 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
INFR4-13597
UC 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.
Lili Yang UCLA Broad Stem Cell Research Center: Photo courtesy Reed Hutchinson PhotoGraphics
When Lili Yang was studying for her PhD she approached her mentor, the Nobel Laureate Dr. David Baltimore, and told him she was thinking about writing her thesis on a combination of gene therapy, immunotherapy and stem cell therapy. She says he looked at her and told her that all three of those approaches had a bad reputation because of so many past failures. He asked her, “Are you sure?” She was.
Fast forward 20 years and Dr. Yang and her team at UCLA have developed stem cell-engineered invariant Natural Killer T (iNKT) cells, a kind of specialized immune system cell, that has the ability to attack and kill a broad range of cancerous cells, while leaving the body’s healthy tissues unharmed.
Thanks to several CIRM grants, Dr. Yang has developed a platform that can use healthy donor blood stem cells to produce clinical scalable “off-the-shelf” iNKT cells. That has led to the creation of Appia Bio, a start-up company, and talks with the FDA about testing a series of iNKT cell products in clinical trials.
Besides developing cell products targeting the more established blood cancer disease indications, Dr. Yang is most excited about using the same platform to generate off-the-shelf iNKT cell products that could target solid tumor cancers that comprise over 90% of the total cancer cases, such as breast, ovarian, prostate, lung, liver, and colon cancers.
“I have this dream that cell therapy can become off-the-shelf, and how this would really help all cancer patients in need. The current cancer cell therapy requires treating patients one-by-one, resulting in a steep price that is hard to afford ($300,000-$500,000 per patient per treatment) and a complex therapy delivery logistics that is challenging to fulfill (coordination of hospitalization, blood collection, cell manufacturing and infusion for each patient). Not everyone lives near a hospital capable of handling such a personalized therapy or can afford such a steep price. If we can make this therapy with centralized manufacturing, pre-quality controlled and ready for wide use then we don’t need to worry about the gender or age or location of the patient. For off-the-shelf therapy, price is also expected to drop down significantly- this will eventually be ready for everyone everywhere.”
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.
Our 2021-22 Annual Report is now online. It’s filled with information about the work we have done over the last year (we are on a fiscal calendar year from July 1 – June 30), the people who have helped us do that work, and some of the people who have benefited from that work. One of those is Dr. Alysson Muotri, a professor in the Departments of Pediatrics and Cellular & Molecular Medicine at the University of California, San Diego.
Dr. Alysson Muotri, in his lab at UCSD
For Dr. Alysson Muotri, trying to unlock the secrets of the brain isn’t just a matter of scientific curiosity, it’s personal. He has a son with autism and Dr. Muotri is looking for ways to help him, and millions of others like him around the world.
He created the Tooth Fairy project where parents donated more than 3,000 baby teeth from children with autism and children who are developing normally. Dr. Muotri then turned cells from those teeth into neurons, the kind of brain cell affected by autism. He is using those cells to try and identify how the brain of a child with autism differs from a child who is developing normally.
“We’ve been using cells from this population to see what are the alterations (in the gene) and if we can revert them back to a normal state. If you know the gene that is affected, and autism has a strong genetic component, by genome sequencing you can actually find what are the genes that are affected and in some cases there are good candidates for gene therapy. So, you just put the gene back. And we can see that in the lab where we are correcting the gene that is mutated, the networks start to function in a way that is more neurotypical or normal. We see that as highly promising, there’s a huge potential here to help those individuals.”
He is also creating brain organoids, three-dimensional structures created from stem cells that mimic some of the actions and activities of the brain. Because these are made from human cells, not mice or other animals, they may be better at indicating if new therapies have any potential risks for people.
“We can test drugs in the brain organoids of the person and see if it works, see if there’s any toxicity before you actually give the drug to a person, and it will save us time and money and will increase our knowledge about the human brain.”
He says he still gets excited seeing how these cells work. “It’s amazing, it’s a miracle. Every time I see it, it’s like seeing dolphins in the sea because it’s so beautiful.”
Dr. Muotri is also a big proponent of diversity, equity and inclusion in scientific research. He says in the past it was very much a top-down model with scientists deciding what was important. He says we need to change that and give patients and communities a bigger role in shaping the direction of research.
“I think this is something we scientists have to learn, how to incorporate patients in our research. These communities are the ones we are studying, and we need to know what they want and not assume that what we want is what they want. They should be consulted on our grants, and they should participate in the design of our experiments. That is the future.”
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.
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.
The Stem Cellar 