Rare disease gets go-ahead to run clinical trial

crf

A young girl with cystinosis: Photo courtesy CRF

Cystinosis is one of those diseases most people have never heard of and should be very grateful they haven’t. It’s rare – affecting only around 500 children and young adults in the US and just 2,000 people worldwide – but it’s nasty. Up to now the treatments for it have been very limited. But a new clinical trial, just given the go-ahead by the Food and Drug Administration (FDA), could help change that.

Cystinosis usually strikes children before they are two years old and can lead to end stage kidney failure before their tenth birthday. It is caused by a genetic mutation that allows an amino acid, cysteine, to build up in and damage the kidneys, eyes, liver, muscles, pancreas and brain.

There is one approved therapy, cysteamine, but this only delays progression of the disease, has severe side effects and people taking it still require kidney transplants, and develop diabetes, neuromuscular disorders and hypothyroidism.

All those are reasons why, in September 2016, the CIRM Board approved $5.2 million for U.C. San Diego researcher Stephanie Cherqui, Ph.D. and her team to try a different approach. Their goal is to take blood stem cells from people with cystinosis, genetically-modify them to remove the mutation that causes the disease, then return them to the patient. The hope is that the modified blood stem cells will create a new, healthy, blood system free of the disease.

Results from pre-clinical work testing this approach in mice have been so encouraging that the FDA has given the go-ahead for that work to now be tested in people.

In a news release Nancy Stack, the Founder and President of the Cystinosis Research Foundation (CRF), the largest provider of grants for cystinosis research in the world, says this is exciting news for a community that has been waiting for a breakthrough:

“We are thrilled that CRF’s dedication to funding Dr. Cherqui’s work has resulted in FDA approval for the first-ever stem cell and gene therapy treatment for individuals living with cystinosis. This approval from the FDA brings us one step closer to what we believe will be a cure for cystinosis and will be the answer to my daughter Natalie’s wish made fifteen years ago, ‘to have my disease go away forever.’ We are so thankful to our donors and our cystinosis families who had faith and believed this day would come.”

Dr. Cherqui says if this is successful it could help more than just people with cystinosis:

“We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis,. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders. If so, CRF, through their years of support will have helped an untold number of patients with untreatable, debilitating diseases.”

Those with questions on the trials can call toll free: 844-317-7836 (STEM) and/or visit www.cystinosisresarch.org

Using 3D printer to develop treatment for spinal cord injury

3d-printed-device

3D printed device

Spinal cord injuries (SCIs) affect approximately 300,000 Americans, with about 18,000 new cases occurring per year. One of these patients, Jake Javier, who we have written about many times over the past several years, received ten million stem cells as part of a CIRM-funded clinical trial and a video about his first year at Cal Poly depicts how these injuries can impact someone’s life.

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.

Scientists at UC San Diego’s School of Medicine and Institute of Engineering in Medicine have made critical progress in providing SCI patients with hope towards a more comprehensive and longer lasting treatment option.

shaochen chen

Prof. Shaochen Chen and his 3D printer

In a study partially funded by CIRM and published in Nature Medicine, Dr. Mark Tuszynski’s and Dr. Shaochen Chen’s groups used a novel 3D printing method to grow a spinal cord in the lab.

Previous studies have seen some success in lab grown neurons or nerve cells, improving SCI in animal models. This new study, however, is innovative both for the speed at which the neurons are printed, and the extent of the neuronal network that is produced.

To achieve this goal, the scientists used a biological scaffold that directs the growth of the neurons so they grow to the correct length and generate a complete neuronal network. Excitingly, their 3D printing technology was so efficient that they were able to grow implants for an animal model in 1.6 seconds, and a human-sized implant in just ten minutes, showing that their technology is scalable for injuries of different sizes.

When they tested the spinal cord implants in rats, they found that not only did the implant repair the damaged spinal cord tissue, but it also provided sustained improvement in motor function up to six months after implantation.

Just as importantly, they also observed that blood vessels had infiltrated the implanted tissue. The absence of vascularized tissue is one of the main reasons engineered implants do not last long in the host, because blood vessels are necessary to provide nutrients and support tissue growth. In this case, the animal’s body solved the problem on its own.

In a press release, one of the co-first authors of the paper, Dr. Kobi Koffler, states the importance and novelty of this work:

“This marks another key step toward conducting clinical trials to repair spinal cord injuries in people. The scaffolding provides a stable, physical structure that supports consistent engraftment and survival of neural stem cells. It seems to shield grafted stem cells from the often toxic, inflammatory environment of a spinal cord injury and helps guide axons through the lesion site completely.”

In order to make this technology viable for human clinical trials, the scientists are testing their technology in larger animal models before moving into humans, as well as investigating how to improve the longevity of the neuronal network by introducing proteins into the scaffolds.

 

 

71 for Proposition 71

Proposition 71 is the state ballot initiative that created California’s Stem Cell Agency. This month, the Agency reached another milestone when the 71st clinical trial was initiated in the CIRM Alpha Stem Cell Clinics (ASCC) Network. The ASCC Network deploys specialized teams of doctors, nurses and laboratory technicians to conduct stem cell clinical trials at leading California Medical Centers.

StateClinics_Image_CMYK

These teams work with academic and industry partners to support patient-centered for over 40 distinct diseases including:

  • Amyotrophic Lateral Sclerosis (ALS)
  • Brain Injury & Stroke
  • Cancer at Multiple Sites
  • Diabetes Type 1
  • Eye Disease / Blindness Heart Failure
  • HIV / AIDS
  • Kidney Failure
  • Severe Combined Immunodeficiency (SCID)
  • Sickle Cell Anemia
  • Spinal Cord Injury

These clinical trials have treated over 400 patients and counting. The Alpha Stem Cell Clinics are part of CIRM’s Strategic Infrastructure. The Strategic Infrastructure program which was developed to support the growth of stem cell / regenerative medicine in California. A comprehensive update of CIRM’s Infrastructure Program was provided to our Board, the ICOC.

CIRM’s infrastructure catalyzes stem cell / regenerative medicine by providing resources to all qualified researchers and organizations requiring specialized expertise. For example, the Alpha Clinics Network is supporting clinical trials from around the world.

Many of these trials are sponsored by commercial companies that have no CIRM funding. To date, the ASCC Network has over $27 million in contracts with outside sponsors. These contracts serve to leverage CIRMs investment and provide the Network’s medical centers with a diverse portfolio of clinical trials to address patients’’ unmet medical needs.

Alpha Clinics – Key Performance Metrics

  • 70+ Clinical Trials
  • 400+ Patients Treated
  • 40+ Disease Indications
  • Over $27 million in contracts with commercial sponsors

The CIRM Alpha Stem Cell Clinics and broader Infrastructure Programs are supporting stem cell research and regenerative medicine at every level, from laboratory research to product manufacturing to delivery to patients. This infrastructure has emerged to make California the world leader in regenerative medicine. It all started because California’s residents supported a ballot measure and today we have 71 clinical trials for 71.

 

 

Stem Cell Agency Invests in New Immunotherapy Approach to HIV, Plus Promising Projects Targeting Blindness and Leukemia

HIV AIDS

While we have made great progress in developing therapies that control the AIDS virus, HIV/AIDS remains a chronic condition and HIV medicines themselves can give rise to a new set of medical issues. That’s why the Board of the California Institute for Regenerative Medicine (CIRM) has awarded $3.8 million to a team from City of Hope to develop an HIV immunotherapy.

The City of Hope team, led by Xiuli Wang, is developing a chimeric antigen receptor T cell or CAR-T that will enable them to target and kill HIV Infection. These CAR-T cells are designed to respond to a vaccine to expand on demand to battle residual HIV as required.

Jeff Sheehy

CIRM Board member Jeff Sheehy

Jeff Sheehy, a CIRM Board member and patient advocate for HIV/AIDS, says there is a real need for a new approach.

“With 37 million people worldwide living with HIV, including one million Americans, a single treatment that cures is desperately needed.  An exciting feature of this approach is the way it is combined with the cytomegalovirus (CMV) vaccine. Making CAR T therapies safer and more efficient would not only help produce a new HIV treatment but would help with CAR T cancer therapies and could facilitate CAR T therapies for other diseases.”

This is a late stage pre-clinical program with a goal of developing the cell therapy and getting the data needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial.

The Board also approved three projects under its Translation Research Program, this is promising research that is building on basic scientific studies to hopefully create new therapies.

  • $5.068 million to University of California at Los Angeles’ Steven Schwartz to use a patient’s own adult cells to develop a treatment for diseases of the retina that can lead to blindness
  • $4.17 million to Karin Gaensler at the University of California at San Francisco to use a leukemia patient’s own cells to develop a vaccine that will stimulate their immune system to attack and destroy leukemia stem cells
  • Almost $4.24 million to Stanford’s Ted Leng to develop an off-the-shelf treatment for age-related macular degeneration (AMD), the leading cause of vision loss in the elderly.

The Board also approved funding for seven projects in the Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.

Application Title Institution CIRM Committed Funding
DISC2-10979 Universal Pluripotent Liver Failure Therapy (UPLiFT)

 

Children’s Hospital of Los Angeles $1,297,512

 

DISC2-11105 Pluripotent stem cell-derived bladder epithelial progenitors for definitive cell replacement therapy of bladder cancer

 

Stanford $1,415,016
DISC2-10973 Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases

 

U.C. San Diego $1,160,648
DISC2-11070 Drug Development for Autism Spectrum Disorder Using Human Patient iPSCs

 

Scripps $1,827,576
DISC2-11183 A screen for drugs to protect against chemotherapy-induced hearing loss, using sensory hair cells derived by direct lineage reprogramming from hiPSCs

 

University of Southern California $833,971
DISC2-11199 Modulation of the Wnt pathway to restore inner ear function

 

Stanford $1,394,870
DISC2-11109 Regenerative Thymic Tissues as Curative Cell Therapy for Patients with 22q11 Deletion Syndrome

 

Stanford $1,415,016

Finally, the Board approved the Agency’s 2019 research budget. Given CIRM’s new partnership with the National Heart, Lung, Blood Institute (NHLBI) to accelerate promising therapies that could help people with Sickle Cell Disease (SCD) the Agency is proposing to set aside $30 million in funding for this program.

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Congresswoman Barbara Lee (D-CA 13th District)

“I am deeply grateful for organizations like CIRM and NHLBI that do vital work every day to help people struggling with Sickle Cell Disease,” said Congresswoman Barbara Lee (D-CA 13th District). “As a member of the House Appropriations Subcommittee on Labor, Health and Human Services, and Education, I know well the importance of this work. This innovative partnership between CIRM and NHLBI is an encouraging sign of progress, and I applaud both organizations for their tireless work to cure Sickle Cell Disease.”

Under the agreement CIRM and the NHLBI will coordinate efforts to identify and co-fund promising therapies targeting SCD.  Programs that are ready to start an IND-enabling or clinical trial project for sickle cell can apply to CIRM for funding from both agencies. CIRM will share application information with the NHLBI and CIRM’s Grants Working Group (GWG) – an independent panel of experts which reviews the scientific merits of applications – will review the applications and make recommendations. The NHLBI will then quickly decide if it wants to partner with CIRM on co-funding the project and if the CIRM governing Board approves the project for funding, the two organizations will agree on a cost-sharing partnership for the clinical trial. CIRM will then set the milestones and manage the single CIRM award and all monitoring of the project.

“This is an extraordinary opportunity to create a first-of-its-kind partnership with the NHLBI to accelerate the development of curative cell and gene treatments for patients suffering with Sickle Cell Disease” says Maria T. Millan, MD, President & CEO of CIRM. “This allows us to multiply the impact each dollar has to find relief for children and adults who battle with this life-threatening, disabling condition that results in a dramatically shortened lifespan.  We are pleased to be able to leverage CIRM’s acceleration model, expertise and infrastructure to partner with the NHLBI to find a cure for this condition that afflicts 100,000 Americans and millions around the globe.”

The budget for 2019 is:

Program type 2019
CLIN1 & 2

CLIN1& 2 Sickle Cell Disease

$93 million

$30 million

TRANSLATIONAL $20 million
DISCOVER $0
EDUCATION $600K

 

 

A cancer therapy developed at a CIRM Alpha Stem Cell Clinic tests its legs against breast cancer

Breast cancer cells

Three-dimensional culture of human breast cancer cells, with DNA stained blue and a protein on the cell surface membrane stained green. Image courtesy The National Institutes of Health

A Phase 1 clinical trial co-sponsored by CIRM and Oncternal Therapeutics, has started treating patients at UC San Diego (UCSD). The goal of the trial is to test the safety and anti-tumor activity of the Oncternal-developed drug, cirmtuzumab, in treating breast cancer.

Breast cancer is the second most common cancer to occur in women, regardless of race or ethnicity. More than 260,000 new cases are expected to be diagnosed this year in the United States alone. Typically, breast cancer cases are treated by a combination of surgery to remove the tumor locally, followed by some kind of systemic treatment, like chemotherapy, which can eliminate cancer cells in other parts of the body. In certain cases, however, surgery might not be a feasible option. Cirmtuzumab may be a viable option for these patients.

The drug acts by binding to a protein called ROR1, which is highly abundant on the surface of cancer cells. By blocking the protein Cirmtuzumab is able to promote cell death, stopping the cancer from spreading around the body.

Because ROR1 is also found on the surface of healthy cells there were concerns using cirmtuzumab could lead to damage to healthy tissue. However, a previous study revealed that using this kind of approach, at least in a healthy non-human primate model did not lead to any adverse clinical symptoms. Therefore, this protein is a viable target for cancer treatment and is particularly promising because it is a marker of many different types of cancers including leukemia, lung cancer and breast cancer.

Phase 1 clinical trials generally enroll a small number of patients who have do not have other treatment options. The primary goals are to determine if this approach is safe, if it causes any serious side-effects, what is the best dosage of the drug and how the drug works in the body. This clinical trial will enroll up to 15 patients who will receive cirmtuzumab in combination with paclitaxel (Taxol), a vetted chemotherapy drug, for six months.

Earlier this year, a similar clinical trial at UCSD began to test the effectiveness a of cirmtuzumab-based combination therapy to treat patients with B-cell cancers such as chronic lymphocytic leukemia. This trial was also partially funded by CIRM.

In a press release, Dr. Barbara Parker, the co-lead on this study states:

“Our primary objective, of course, is to determine whether the drug combination is safe and tolerable and to measure its anti-tumor activity. If it proves safe and shows effectiveness against breast cancer, we can progress to subsequent trials to determine how best to use the drug combination.”

Research Targeting Prostate Cancer Gets Almost $4 Million Support from CIRM

Prostate cancer

A program hoping to supercharge a patient’s own immune system cells to attack and kill a treatment resistant form of prostate cancer was today awarded $3.99 million by the governing Board of the California Institute for Regenerative Medicine (CIRM)

In the U.S., prostate cancer is the second most common cause of cancer deaths in men.  An estimated 170,000 new cases are diagnosed each year and over 29,000 deaths are estimated in 2018.  Early stage prostate cancer is usually managed by surgery, radiation and/or hormone therapy. However, for men diagnosed with castrate-resistant metastatic prostate cancer (CRPC) these treatments often fail to work and the disease eventually proves fatal.

Poseida Therapeutics will be funded by CIRM to develop genetically engineered chimeric antigen receptor T cells (CAR-T) to treat metastatic CRPC. In cancer, there is a breakdown in the natural ability of immune T-cells to survey the body and recognize, bind to and kill cancerous cells. Poseida is engineering T cells and T memory stem cells to express a chimeric antigen receptor that arms these cells to more efficiently target, bind to and destroy the cancer cell. Millions of these cells are then grown in the laboratory and then re-infused into the patient. The CAR-T memory stem cells have the potential to persist long-term and kill residual cancer calls.

“This is a promising approach to an incurable disease where patients have few options,” says Maria T. Millan, M.D., President and CEO of CIRM. “The use of chimeric antigen receptor engineered T cells has led to impressive results in blood malignancies and a natural extension of this promising approach is to tackle currently untreatable solid malignancies, such as castrate resistant metastatic prostate cancer. CIRM is pleased to partner on this program and to add it to its portfolio that involves CAR T memory stem cells.”

Poseida Therapeutics plans to use the funding to complete the late-stage testing needed to apply to the Food and Drug Administration for the go-ahead to start a clinical trial in people.

Quest Awards

The CIRM Board also voted to approve investing $10 million for eight projects under its Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.

Among those approved for funding are:

  • Eric Adler at UC San Diego is using genetically modified blood stem cells to treat Danon Disease, a rare and fatal condition that affects the heart
  • Li Gan at the Gladstone Institutes will use induced pluripotent stem cells to develop a therapy for a familial form of dementia
  • Saul Priceman at City of Hope will use CAR-T therapy to develop a treatment for recurrent ovarian cancer

Because the amount of funding for the recommended applications exceeded the money set aside, the Application Subcommittee voted to approve partial funding for two projects, DISC2-11192 and DISC2-11109 and to recommend, at the next full Board meeting in October, that the projects get the remainder of the funds needed to complete their research.

The successful applications are:

 

APPLICATION

 

TITLE

 

INSTITUTION

CIRM COMMITTED FUNDING
DISC2-11131 Genetically Modified Hematopoietic Stem Cells for the

Treatment of Danon Disease

 

 

U.C San Diego

 

$1,393,200

 

DISC2-11157 Preclinical Development of An HSC-Engineered Off-

The-Shelf iNKT Cell Therapy for Cancer

 

 

U.C. Los Angeles

 

$1,404,000

DISC2-11036 Non-viral reprogramming of the endogenous TCRα

locus to direct stem memory T cells against shared

neoantigens in malignant gliomas

 

 

U.C. San Francisco

 

$900,000

DISC2-11175 Therapeutic immune tolerant human islet-like

organoids (HILOs) for Type 1 Diabetes

 

 

Salk Institute

 

$1,637,209

DISC2-11107 Chimeric Antigen Receptor-Engineered Stem/Memory

T Cells for the Treatment of Recurrent Ovarian Cancer

 

 

City of Hope

 

$1,381,104

DISC2-11165 Develop iPSC-derived microglia to treat progranulin-

deficient Frontotemporal Dementia

 

 

Gladstone Institutes

 

$1,553,923

DISC2-11192 Mesenchymal stem cell extracellular vesicles as

therapy for pulmonary fibrosis

 

 

U.C. San Diego

 

$865,282

DISC2-11109 Regenerative Thymic Tissues as Curative Cell

Therapy for Patients with 22q11 Deletion Syndrome

 

 

Stanford University

 

$865,282

 

 

Patients at the heart of Alpha Stem Cell Clinics Symposium

I have been to a lot of stem cell conferences over the years and there’s one recent trend I really like: the growing importance and frequency of the role played by patient advocates.

There was a time, not so long ago, when having a patient advocate speak at a scientific conference was almost considered a novelty. But more and more it’s being seen for what it is, an essential item on the agenda. After all, they are the reason everyone at that conference is working. It’s all about the patients.

That message was front and center at the 3rd Annual CIRM Alpha Stem Cell Clinics Network Symposium at UCLA last week. The theme of the symposium was the Delivery of Stem Cell Therapeutics to Patients. There were several fascinating scientific presentations, highlighting the progress being made in stem cell research, but it was the voices of the patient advocates that were loudest and most powerful.

First a little background. The CIRM Alpha Stem Cell Clinics Network consists of six major medical centers – UCLA/UC Irvine (joint hosts of this conference), UC San Diego, City of Hope, UC San Francisco and UC Davis. The Network was established with the goal of accelerating the development and delivery of high-quality stem cell clinical trials to patients. This meeting brought together clinical investigators, scientists, patients, patient advocates, and the public in a thoughtful discussion on how novel stem cell therapies are now a reality.

It was definitely thoughtful. Gianna McMillan, the Co-Founder and Executive Director of “We Can, Pediatric Brain Tumor Network” set the tone with her talk titled, “Tell Me What I Need to Know”. At age 5 her son was diagnosed with a brain tumor, sending her life into a tailspin. The lessons she learned from that experience – happily her son is now a healthy young man – drive her determination to help others cope with similar situations.

Calling herself an “in the trenches patient advocate champion” she says:

“In the old days doctors made decisions on behalf of the patients who meekly and gratefully did what they were told. It’s very different today. Patients are better informed and want to be partners in the treatment they get. But yet this is not an equal partnership, because subjects (patients) are always at a disadvantage.”

She said patients often don’t speak the language of the disease or understand the scientific jargon doctors use when they talk about it. At the same time patients are wrestling with overwhelming emotions such as fear and anxiety because their lives have been completely overturned.

Yet she says a meaningful partnership is possible as long as doctors keep three basic questions in mind when dealing with people who are getting a new diagnosis of a life-threatening or life-changing condition:

  • Tell me what I need to know
  • Tell me in language I can understand
  • Tell me again and again

It’s a simple formula, but one that is so important that it needs to be stated over and over again. “Tell me again. And again. And again.”

David Mitchell, the President and Founder of Patients for Affordable Drugs, tackled another aspect of the patient experience: the price of therapies. He posed the question “What good is a therapy if no one can afford it?”

David’s organization focuses on changing policy at the state and federal level to lower the price of prescription drugs. He pointed out that many other countries charge lower prices for drugs than the US, in part because those countries’ governments negotiate directly with drug companies on pricing.

He says if we want to make changes in this country that benefit patients then patient have to become actively involved in lobbying their government, at both the state and local level, for more balanced prices, and in supporting candidates for public office who support real change in drug-pricing policy.

It’s encouraging to see that just as the field of stem cell research is advancing so too is the prominence of the patient’s voice. The CIRM Alpha Stem Cell Clinics Network is pushing the field forward in exciting ways, and the patients are becoming an increasingly important, and vital part of that. And that is as it should be.

CIRM-funded clinical trial takes a combination approach to treating deadly blood cancers

Stained blood smear shows enlarged chronic lymphocytic leukemia cells among normal red blood cells. (UCSD Health)

A diagnosis of cancer often means a tough road ahead, with surgery, chemotherapy and radiation used to try and kill the tumor. Even then, sometimes cancer cells manage to survive and return later, spreading throughout the body. Now researchers at UC San Diego and Oncternal Therapeutics are teaming up with a combination approach they hope will destroy hard-to-kill blood cancers like leukemia.

The combination uses a monoclonal antibody called cirmtuzumab (so called because CIRM funding helped develop it) and a more traditional anti-cancer therapy called ibrutinib. Here’s how it is hoped this approach will work.

Ibrutinib is already approved by the US Food and Drug Administration (FDA) to treat blood cancers such as leukemia and lymphoma. But while it can help, it doesn’t always completely eradicate all the cancer cells. Some cancer stem cells are able to lie dormant during treatment and then start proliferating and spreading the cancer later. That’s why the team are pairing ibrutinib with cirmtuzumab.

In a news release announcing the start of the trial, UCSD’s Dr. Thomas Kipps,  said they hope this one-two punch combination will be more effective.

Thomas Kipps, UCSD

“As a result {of the failure to kill all the cancer cells}, patients typically need to take ibrutinib indefinitely, or until they develop intolerance or resistance to this drug. Cirmtuzumab targets leukemia and cancer stem cells, which are like the seeds of cancer. They are hard to find and difficult to destroy. By blocking signaling pathways that promote neoplastic-cell growth and survival, cirmtuzumab may have complementary activity with ibrutinib in killing leukemia cells, allowing patients potentially to achieve complete remissions that permit patients to stop therapy altogether.”

Because this is an early stage clinical trial, the goal is to first make sure the approach is safe, and second to identify the best dose and treatment schedule for patients.

The researchers hope to recruit 117 patients around the US. Some will get the cirmtuzumab and ibrutinib combination, some will get ibrutinib alone to see if one approach is more effective than the other.

CIRM has a triple investment in this research. Not only did our funding help develop cirmtuzumab, but CIRM is also funding this clinical trial and one of the trial sites is at UCSD, one of the CIRM Alpha Stem Cell Clinics.

CIRM’s Dr. Ingrid Caras says this highlights our commitment to our mission of accelerating stem cell therapies to patients with unmet medical needs.

“Our partnership with UC San Diego and the Alpha Stem Cell Clinics has enabled this trial to more quickly engage potential patient-participants. Being among the first to try new therapies requires courage and CIRM is grateful to the patients who are volunteering to be part of this clinical trial.”


Related Links:

Scientists repair spinal cord injuries in monkeys using human stem cells

Human neuronal stem cells extend axons (green). (Image UCSD)

An exciting development for spinal cord injury research was published this week in the journal Nature Medicine. Scientists from the University of San Diego School of Medicine transplanted human neural progenitor cells (NPCs) into rhesus monkeys that had spinal cord injuries. These cells, which are capable of turning into other cells in the brain, survived and robustly developed into nerve cells that improved the monkeys’ use of their hands and arms.

The scientists grafted 20 million human NPCs derived from embryonic stem cells into two-week-old spinal cord lesions in the monkeys. These stem cells were delivered with growth factors to improve their survival and growth. The monkeys were also treated with immunosuppressive drugs to prevent their immune system from rejecting the human cells.

After nine months, they discovered that the NPCs had developed into nerve cells within the injury site that extended past the injury into healthy tissue. These nerve extensions are called axons, which allow nerves to transmit electrical signals and instructions to other brain cells. During spinal cord injury, nerve cells and their axon extensions are damaged. Scientists have found it difficult to regenerate these damaged cells because of the inhibitory growth environment created at the injury site. You can compare it to the build-up of scar tissue after a heart attack. The heart has difficulty regenerating healthy heart muscle, which is instead replaced by fibrous scar tissue.

Excitingly, the UCSD team was able to overcome this hurdle in their current study. When they transplanted human NPCs with growth factors into the monkeys, they found that the cells were not affected by the inhibitory environment of the injury and were able to robustly develop into nerve cells and send out axon extensions.

Large numbers of human axons (green) emerge from a lesion/graft sites. Many axons travel along the interface (indicated by arrows) between spinal cord white matter (nerve fibers covered with myelin) and spinal cord gray matter (nerves without the whitish myelin sheathing). Image courtesy of Mark Tuszynski, UC San Diego School of Medicine.

The senior scientist on the study, Dr. Mark Tuszynski, explained how their findings in a large animal model are a huge step forward for the field in a UCSD Health news release:

“While there was real progress in research using small animal models, there were also enormous uncertainties that we felt could only be addressed by progressing to models more like humans before we conduct trials with people. We discovered that the grafting methods used with rodents didn’t work in larger, non-human primates. There were critical issues of scale, immunosuppression, timing and other features of methodology that had to be altered or invented. Had we attempted human transplantation without prior large animal testing, there would have been substantial risk of clinical trial failure, not because neural stem cells failed to reach their biological potential but because of things we did not know in terms of grafting and supporting the grafted cells.”

Dr. Tuszynski is a CIRM-grantee whose earlier research involved optimizing stem cell treatments for rodent models of spinal cord injury. We’ve blogged about that research previously on the Stem Cellar here and here.

Tuszynski recently was awarded a CIRM discovery stage research grant to develop a candidate human neural stem cell line that is optimized to repair the injured spinal cord and can be used in human clinical trials. He expressed cautious optimism about the future of this treatment for spinal cord injury patients emphasizing the need for patience and more research before arriving at clinical trials:

“We seem to have overcome some major barriers, including the inhibitory nature of adult myelin against axon growth. Our work has taught us that stem cells will take a long time to mature after transplantation to an injury site, and that patience will be required when moving to humans. Still, the growth we observe from these cells is remarkable — and unlike anything I thought possible even ten years ago. There is clearly significant potential here that we hope will benefit humans with spinal cord injury.”


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Alpha clinics and a new framework for accelerating stem cell treatments

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Last week, at the World Stem Cell Summit in Miami, CIRM took part in a panel discussion about the role and importance of Alpha Clinics in not just delivering stem cell therapies, but in helping create a new, more collaborative approach to medicine. The Alpha Clinic concept is to create  a network of top medical centers that specialize in delivering stem cell clinical trials to patients.

The panel was moderated by Dr. Tony Atala, Director of the Wake Forest Institute for Regenerative Medicine. He said the term Alpha Clinic came from CIRM and the Alpha Stem Cell Clinic Network that we helped create. That network now has five specialist health care centers that deliver stem cell therapies to patients: UC San Diego, UCLA/UC Irvine, City of Hope, UC Davis, and  UCSF/Children’s Hospital Oakland.

This is a snapshot of that conversation.

Alpha Clinics Advancing Stem Cell Trials

Dr. Maria Millan, CIRM’s President & CEO:

“The idea behind the Alpha Stem Cell Clinic Network is that CIRM is in the business of accelerating treatments to patients with unmet medical needs. We fund research from the earliest discovery stage to clinical trials. What was anticipated is that, if the goal is to get these discoveries into the clinics then we’ll need a specific set of expertise and talents to deliver those treatments safely and effectively, to gather data from those trials and move the field forward. So, we set out to create a learning network, a sharing network and a network that is more than the sum of its parts.”

Dr. Joshua Hare,  Interdisciplinary Stem Cell Institute, University of Miami, said that idea of collaboration is critical to advancing the field:

 

“What we learned is that having the Alpha Stem Cell Clinic concept helps investigators in other areas learn from what earlier researchers have done, helping accelerate their work.

For example, we have had a lot of experience in working with rare diseases and we can use the experience we have in treating one disease area in working in others. This shared experience can help us develop deeper understanding in terms of delivering therapies and dosing.”

Susan Solomon, CEO New York Stem Cell Foundation Research Institute. NYSCF has several clinical trials underway. She says in the beginning it was hard finding reputable clinics that could deliver these potentially ground breaking but still experimental therapies:

 

“My motivation was born out of my own frustration at the poor choices we had in dealing with some devastating diseases, so in order to move things ahead we had to have an alpha clinic that is not just doing clinical trials but is working to overcome obstacles in the field.”

Greg Simon represented the, Biden Cancer Initiative, whose  mission is to develop and drive implementation of solutions to accelerate progress in cancer prevention, detection, diagnosis, research, and care, and to reduce disparities in cancer outcomes. He says part of the problem is that people think there are systems already in place that promote collaboration and cooperation, but that’s not really the case.  

 

“In the Cancer Moonshot and the Biden Cancer Initiative we are trying to create the cancer research initiative that people think we already have. People think doctors share knowledge. They don’t. People think they can just sign up for clinical trials. They can’t. People think there are standards for describing a cancer. There aren’t. So, all the things you think you know about the science behind cancer are wrong. We don’t have the system people think is in place. But we want to create that.

If we are going to have a unified system we need common standards through cancer research, shared knowledge, and clinical trial reforms. All my professional career it was considered unethical to refer to a clinical trial as a treatment, it was research. That’s no longer the case. Many people are now told this is your last best hope for treatment and it’s changed the way people think about clinical trials.”

The Process

Maria Millan says we are seeing these kinds of change – more collaboration, more transparency –  taking place across the board:

“We see the research in academic institutions that then moved into small companies that are now being approved by the FDA. Academic centers, in conjunction with industry partners, are helping create networks and connections that advance therapies.

This gives us the opportunity to have clinical programs and dialogues about how we can get better, how we can create a more uniform, standard approach that helps us learn from each trial and develop common standards that investigators know have to be in place.

Within the CIRM Alpha Stem Cell Clinic Network the teams coming in can access what we have pulled together already – a database of 20 million patients, a single IRB approval, so that if a cliinical trial is approved for one Alpha Clinic it can also be offered at another.”

Greg Simon says to see the changes really take hold we need to ensure this idea of collaboration starts at the very beginning of the chain:

“If we don’t have a system of basic research where people share data, where people are rewarded for sharing data, journals that don’t lock up the data behind a paywall. If we don’t have that system, we don’t have the ability to move therapies along as quickly as we could.

“Nobody wants to be the last person to die from a cancer that someone figured out a treatment for a year earlier. It’s not that the science is so hard, or the diseases are so hard, it the way we approach them that’s so hard. How do we create the right system?”

More may not necessarily be better

Susan Solomon:

“There are tremendous number of advances moving to the clinic, but I am concerned about the need for more sharing and the sheer number of clinical trials. We have to be smart about how we do our work. There is some low hanging fruit for some clinical trials in the cancer area, but you have to be really careful.”

Greg Simon

“We have too many bad trials, we don’t need more, we need better quality trials.

We have made a lot of progress in cancer. I’m a CLL survivor and had zero problems with the treatment and everything went well.

We have pediatric cancer therapies that turned survival from 10 % to 80%. But the question is why doesn’t more progress happen. We tend to get stuck in a way of thinking and don’t question why it has to be that way. We think of funding because that’s the way funding cycles work, the NIH issues grants every year, so we think about research on a yearly basis. We need to change the cycle.”

Maria Millan says CIRM takes a two pronged approach to improving things, renovating and creating:

“We renovate when we know there are things already in place that can be improved and made better; and we create if there’s nothing there and it needs to be created. We want to be as efficient as we can and not waste time and resources.”

She ended by saying one of the most exciting things today is that the discussion now has moved to how we are going to cover this for patients. Greg Simon couldn’t agree more.

“The biggest predictor of survivability of cancer is health insurance. We need to do more than just develop treatments. We need to have a system that enables people to get access to these therapies.”