Blood stem cell transplantation following high dose chemotherapy is standard of care and potentially curative for aggressive forms of lymphoma. However, this treatment regimen is limited by severe toxicity and life-threatening complications due to delayed recovery of the blood system and vascular related damage of multiple organs.
This brings the number of clinical trials funded by CIRM to 86.
The Board awarded $15,000,000 to Dr. Paul Finnegan and Angiocrine Bioscience to test AB-205, human endothelial cells engineered to express a pro-survival factor.
Prior data suggest that, in the setting of chemotherapy and stem cell transplantation, AB-205 cell therapy can accelerate the recovery of the blood system and protects from toxicity by enhancing the recovery from vascular damage. AB-205 is being studied in a Phase 3 trial in adults with lymphoma undergoing high-dose chemotherapy and autologous blood stem cell transplant.
“If successful, this approach can overcome hurdles to the success of chemotherapy and blood stem cell transplantation for the treatment of advanced blood cancer,” says Dr. Maria T. Millan, President and CEO of CIRM. “This Phase 3 trial is the culmination of preclinical research and the initial clinical trial previously funded by CIRM.”
Lymphoma is the most common blood cancer and one of the most common cancers in the United States, accounting for about 4% of all cancers according to the American Cancer Society and the 6th most commonly diagnosed cancer among men and women in California. It is estimated that there will be 89,010 new cases of lymphoma and 21,170 lymphoma related deaths in the US in 2022 alone. In California, it is estimated that there will be over 9,250 new cases of lymphoma with over 2,100 deaths.
“Angiocrine Bioscience is honored to be awarded this grant from CIRM to support our AB-205 Phase 3 trial,” commented Angiocrine CEO Dr. Paul Finnegan. “CIRM has been an instrumental partner in our development of AB-205, a novel therapeutic that acts on the patients’ endogenous stem cell niches. The grant award will considerably aid in our effort to bring forth a solution to the unmet need of transplant-related complications.”
A spinal cord injury (SCI) is devastating, changing a person’s life in an instant. Every year, around the world, between 250,000 and 500,000 people suffer a spinal cord injury. Most of these are caused by trauma to the spinal column, thereby affecting the spinal cord’s ability to send and receive messages from the brain to the body’s systems that control sensory, motor and autonomic function below the level of injury.
Currently, there is nothing that completely reverses SCI damage and most treatment is aimed at rehabilitation and empowering patients to lead as normal a life as possible under the circumstances. Improved treatment options are necessary both to improve patients’ overall quality of life, and to reduce associated healthcare costs.
In 2010, the Geron trial became not only the first clinical trial to be funded by the California Institute for Regenerative Medicine (CIRM), but the first clinical trial in the world using embryonic stem cells.
By 2014, Asterias Biotherapeutics (now Lineage Cell Therapeutics Inc.), acquired the cell therapy assets of Geron and launched its Phase 1/2a clinical trial with the goal of determining the safety of the therapy and the optimal dose of cells to transplant into patients.
In 2016, Jake Javier became the fifth patient to participate in the revived Asterias trial. Regular readers of our blog will remember that Jake is the young man who broke his neck the day before he graduated high school, leaving him paralyzed from the upper chest down.
After enrolling in the CIRM-funded Asterias clinical trial, and receiving a transplant of ten million stem cells, Jake regained enough use of his arms and hands to be able to go to Cal Poly and start his life over.
This video highlights the struggles and challenges he faced in his first year, and his extraordinary spirit in overcoming them.
Video courtesy of Matt Yoon and his team at Cal Poly
Today, Jake is set to graduate from Duke University with his master’s degree in Biomedical Engineering, with plans to help those impacted by neurological injuries or disease.
Watch the video below to learn more about Jake’s personal perspective on his clinical trial participation, the OPC1 clinical study, his future plans and his message to the SCI community.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. Now, new research using 3D organoid models of the eye has uncovered clues as to what happens in AMD, and how to stop it.
In AMD, a person loses their central vision because the light sensitive cells in the macula, a part of the retina, are damaged or destroyed. This impacts a person’s ability to see fine details, recognize faces or read small print, and means they can no longer drive.
AMD causes blurry and distorted vision
No one is quite sure what causes AMD, but in a study in the journal Nature Communications, German researchers used miniature human retina organoids to get some clues.
Building a better model for research
Organoids are 3D models made from human cells that are grown in the lab. Because they have some of the characteristics of a human organ—in this case the retina—they help researchers better understand what is happening in the AMD-affected eye.
In this study they found that photoreceptors, the light sensitive cells at the back of the retina, were missing but there was no sign of dead cells in the organoid. This led them to suspect that something called cell extrusion was at play.
Cell extrusion is where a cell exports or sends large particles outside the cell. In this case it appeared that something was causing these photoreceptors to be extruded, leading to the impaired visual ability.
In a news release Mark Karl, one of the authors of the study, said, “This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina. Half of all photoreceptors disappeared from the retinal organoid within ten days, but obviously they did not die in the retina. That made us curious.”
Using snakes to fight AMD
Further research identified two proteins that appeared to play a key role in the process, triggering the degeneration of the retinal organoid. They also tested a potential therapy to see if they could stop the process and save the photoreceptors. The therapy they tried, a snake venom, not only stopped the photoreceptors from being ejected, but it also prevented further damage to the retinal cells.
Karl says this is the starting point for the next step in the research. “This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD.”
CIRM’s fight against blindness
The California Institute for Regenerative Medicine (CIRM) has funded six clinical trials targeting vision loss, including one for AMD. We recently interviewed Dr. Dennis Clegg, one of the team trying to develop a treatment for AMD and he talked about the encouraging results they have seen so far. You can hear that interview on our podcast “Talking ‘Bout (re)Generation.”
Earlier this year, CIRM welcomed many energetic and enthusiastic high school students at the 2022 SPARK Program annual conference in Oakland. The SPARK program is one of the California Institute for Regenerative Medicine’s (CIRM) many programs dedicated to building a diverse and highly-skilled workforce to support the growing regenerative medicine economy right here in California.
At the SPARK conference, a handful of students presented the stem cell research they did over the summer. It was a great opportunity to share their experiences as well as findings to their high school peers.
Just recently, Simran Ovalekar—a 2022 SPARK program intern—had the unique opportunity to share her research and findings with a wider audience, including undergraduate and PhD students at STEM Shadow Day in San Diego. The event aims to provide college prep students from San Diego and Imperial Valley counties with a unique experience to witness the “real world” of work in an engineering or scientific environment.
“At first I was nervous because I understood that I would be presenting not only in front of high school students, but also undergraduates and PhD candidates,” Simran says. “After reviewing my research, I felt solid and excited to present. I absolutely loved working in the lab so I knew all I had to do was be myself and show my enthusiasm.”
During the SPARK summer internship, Simran joined the Sacco Lab to study Duchenne Muscular Dystrophy (DMD) and how stem cells can be used to provide treatment. DMD is a progressive muscle wasting disorder with life expectancy of approximately age 20. There are around 17,000 people, the vast majority of them boys, diagnosed with DMD in the US.
Dr. Sacco’s lab—which has also received CIRM funding—is researching ways to generate healthy adult muscle stem cells using the patient’s own cells to generate healthy skeletal muscle.
For Simran, conducting research for DMD was personal, as her sister was born with a defect affecting the heart.
“When I began this program, I had a superficial understanding of what a stem cell was. Now, however, I am amazed at the possibilities stem cells provide, and with certainty, can say stem cells are the future of medicine.”
After her presentation at STEM Shadow Day, Simran says she received a positive response from attendees and was reminded why she loves science and of her passion for pursuing a career in stem cell research.
“I am looking forward to continue skeletal stem cell research and am even open to experimenting with other avenues of molecular medicine,” Simran says. “I am eager to have the opportunity to pursue the hands-on research I enjoyed this past summer.”
CIRM has also funded a clinical trial for people with DMD. We blogged about that work and how the impact it is having on some people’s lives.
El bebé, Tobi recibió un tratamiento de células madre, financiado por el CIRM, mientras aún estaba en el útero.To read this blog in English, click here.
Michelle y Jeff se llenaron de felicidad cuando se enteraron de que iban a tener un bebé.
Luego, un examen de ultrasonido a las 20 semanas del embarazo reveló que el feto tenía espina bífida, una malformación congénita que ocurre cuando la columna vertebral y la médula espinal no se forman de manera adecuada. La espina bífida puede causar parálisis y otras complicaciones serias.
Se derivó a la pareja a un ensayo clínico en la Universidad de California, Davis, que lleva a cabo la Dra. Diana Farmer, cirujana fetal y neonatal reconocida a nivel internacional, y su colega, el Dr. Aijun Wang.
En este ensayo clínico, que se basó en una previa investigación financiada por el CIRM, se repara el defecto espinal aplicando células madre de una placenta donada, las cuales se insertan en una estructura sintética y se aplican al defecto de la médula espinal mientras el bebé se encuentra todavía en el útero.
El hijo de Michelle y Jeff, Tobi, fue el segundo paciente que recibió este tratamiento. Michelle dijo que la cirugía fue difícil, pero el nacimiento de su bebé valió la pena.
“Cuando lo abrazamos por primera vez dijimos, ‘No puedo creer que hayamos hecho esto. Lo logramos. Lo hicimos sin saber si funcionaría’.”
A los tres meses, el progreso de Tobi parece promisorio. Jeff y Michelle saben que pueden surgir problemas más adelante, pero por ahora se sienten agradecidos de haber formado parte de este ensayo.
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
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.
In a new study, researchers from UC San Francisco and Vanderbilt University Medical Center have identified specific immune cells that cause a potentially lethal heart inflammation -called myocarditis- in a small fraction of patients treated with powerful cancer immunotherapy drugs.
Myocarditis is inflammation of the heart muscle. It can cause chest pain, shortness of breath, and rapid or irregular heart rhythms. Myocarditis can weaken the heart and its electrical system. As a result, the heart’s ability to pump blood declines. In severe cases, myocarditis causes clots and may lead to stroke, heart attack, heart failure and even death.
The form of myocarditis the researchers studied is a rare but deadly side effect of cancer immunotherapy drugs called immune checkpoint inhibitors (ICIs).
ICI is a type of therapy method that can improve the anti-tumor immune response by regulating the activity of T cells. ICI treatment has proven lifesaving for many cancer patients and fewer than one percent of patients who receive ICI develop myocarditis.
However, according to Javid Moslehi, MD, chief of Cardio-Oncology and Immunology for the UCSF Heart and Vascular Center, nearly half of patients who do experience ICI-caused myocarditis die as a result.
Using genetically altered mice to mimic human ICI-caused myocarditis in the new study, the researchers found an excess of immune system cells called CD8 T lymphocytes in the inflamed heart tissue of mice with myocarditis.
“We earlier observed many T cells in patients who had died, but in the mice we performed several key experiments to show that the T lymphocytes really are drivers of the disease process, and not merely innocent bystanders,” Moslehi said. “There are therapeutic implications to this study.”
The results of the study led the researchers to conclude that activation of CD8 T cells is necessary to trigger myocarditis in ICI-treated cancer patients and therefore immunosuppressive therapies that affect CD8 T cells might play a beneficial role.
Their new findings already have led them to begin investigating better ways to prevent and treat myocarditis. The research team already has reported a case study in which they used Abatacept, a rheumatoid arthritis drug that suppresses the activation of CD8 T cells, to successfully treat myocarditis in a cancer patient.
A study by Stanford Medicine researchers in older mice may lead to treatments that help seniors regain muscle strength lost to aging.
Muscle stem cells—which are activated in response to muscle injury to regenerate damaged muscle tissue—lose their potency with age. A study from the National Health and Nutrition Examination Survey showed that five percent of adults aged 60 and over had weak muscle strength, and thirteen percent had intermediate muscle strength.
Now, researchers at Stanford Medicine are seeing that old mice regain the leg muscle strength of younger animals after receiving an antibody treatment that targets a pathway mediated by a molecule called CD47.
CD47 is a protein found on the surface of many cells in the body. Billed as the “don’t eat me” molecule, it is better known as a target for cancer immunotherapy. It’s common on the surface of many cancer cells and protects them from immune cells that patrol the body looking for dysfunctional or abnormal cells.
Stanford researchers are finding that old muscle stem cells may use a similar approach to avoid being targeted by the immune system.
It’s been difficult to determine why muscle stem cells lose their ability to divide rapidly in response to injury or exercise as they age. Dr. Ermelinda Porpiglia, the lead author of the study, used a technique called “single-cell mass cytometry” to study mouse muscle stem cells.
Using the technique, Porpiglia focused on CD47, and found that the molecule was found at high levels on the surface of some muscle stem cells in older mice, but at lower levels in younger animals. Porpiglia also found that high levels of CD47 on the surface of muscle stem cells correlate with a decrease in their function.
“This finding was unexpected because we primarily think of CD47 as an immune regulator,” Porpiglia said. “But it makes sense that, much like cancer cells, aged stem cells might be using CD47 to escape the immune system.”
Testing an Antibody
Further investigation revealed that a molecule called thrombospondin, which binds to CD47 on the surface of the muscle stem cells, suppresses the muscle stem cells’ activity.
Porpiglia showed that an antibody that recognizes thrombospondin and blocks its ability to bind to CD47 dramatically affected the function of muscle stem cells. Cells from older animals divided more robustly when growing in a laboratory dish in the presence of the antibody, and when the antibody was injected into the leg muscles of old mice the animals developed bigger and stronger leg muscles than control animals.
When given prior to injury, the antibody helped the aged animals recover in ways similar to younger mice.
Porpiglia said, “We are hopeful that it might one day be possible to inject an antibody to thrombospondin at specific sites in the body to regenerate muscle in older people or to counteract functional problems due to disease or surgery.”
These results are significant because they could one day make it possible to boost muscle recovery in humans after surgery and reduce the decline in muscle strength as people age, but researchers say more work is needed.
“Rejuvenating the muscle stem cell population in older mice led to a significant increase in strength,” said Dr. Helen Blau, a senior author of the study. “This is a localized treatment that could be useful in many clinical settings, although more work needs to be done to determine whether this approach will be safe and effective in humans.”
CIRM has previously funded work with researchers using CD47 that led to clinical trials targeting cancer. You can read about that work here and here. That work led to the creation of a company, Forty Seven Inc, which was eventually bought by Gilead for $4.9 billion.
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.”
The Stem Cellar 