Identifying the visually impaired patients most likely to benefit from jCyte’s stem cell therapy

We have written about jCyte many times on The Stem Cellar. For one reason, they are showing really encouraging results in their treatment for retinitis pigmentosa (RP). And now they have taken an even deeper dive into those results and identified which patients may be most likely to benefit from the therapy.

RP is a rare genetic disorder that slowly destroys the rods and cones, the light sensing cells in the back of the eye. If you look at the image below the one on the left shows normal vision, the one on the right shows what happens with RP. At first you start to lose night vision, then other parts of your vision are slowly eroded until you are legally blind.

RP starts early, often people are diagnosed in their teens and are legally blind by middle age. There is no treatment, no cure. It’s estimated that as many as 100,000 people in the US have RP, as many as two million worldwide.

That’s where jCyte comes in. They developed jCell, a therapy using adult stem cells that have been changed into human retinal progenitor cells (hRPCs). These are injected into the back of the eye where they secrete small proteins called neurotrophic factors.

Dr. Henry Klassen, one of the founders of jCyte, says jCell works by preserving the remaining photoreceptors in the eye, and helping them bounce back.

“Typically, people think about the disease as a narrowing of this peripheral vision in a very nice granular way, but that’s actually not what happens. What happens in the disease is that patients lose like islands of vision. So, what we’re doing in our tests is actually measuring […] islands that the patients have at baseline, and then what we’re seeing after treatment is that the islands are expanding. It’s similar to the way that one would track, let’s say a tumor, in oncology of course we’re looking for the opposite effect. We’re looking for the islands of vision to expand.”

And in patients treated with jCell those islands of vision did expand. The team followed patients for one-year post treatment and found that patients given the highest dose, six million cells, experienced the biggest improvement and were able to read, on average, 16 more letters on a standard eye chart than they had been before treatment. In comparison people given a sham or placebo treatment only had an improvement of less than two letters.

This group also experienced improvements in their peripheral vision, their ability to distinguish objects in the foreground from the background and were better able to get around in low light.

But that’s not all. Dr. Sunil Srivastava, with the Cleveland Clinic Cole Eye Institute, did a detailed analysis of patients treated in the trial and identified central foveal thickness (CFT- the part of the eye located in the center of the retina) as an important marker for who would be most likely to benefit from jCell. People who started out with a higher CFT score were most likely to get the biggest benefits.

In a news release, jCyte CEO Dr. Shannon Blalock said the findings are really encouraging: “We look forward to working closely with our scientific advisory board and principal investigators to apply these key learnings to our upcoming pivotal study of jCell to optimize its probability of success in an effort to advance the clinical development program of our RMAT designated therapy for RP patients who currently have no treatment options.”

New technique maps out diversity and location of cells in tissue or tumor

Image Description: Alex Marson is part of a team of researchers who developed a new technique to map the specialized diversity and spatial location of individual cells within a tissue or tumor. Photo Credit: Anastasiia Sapon

All the cells in your body work together and each can have a different role. Their individual function not only depends on cell type, but can also depend on their specific location and surroundings.

A CIRM supported and collaborative study at the Gladstone Institutes, UC San Francisco (UCSF), and UC Berkeley has developed a more efficient method than ever before to simultaneously map the specialized diversity and spatial location of individual cells within a tissue or a tumor.

The technique is named XYZeq and involves segmenting a tissue into microscopic regions. Within each of these microscopic grids, each cell’s genetic information is analyzed in order to better understand how each particular cell functions relative to its spacial location.

For this study, the team obtained tissue from mice with liver and spleen tumors. A slice of tissue was then placed on a slide that divides the tissue into hundreds of “microwells” the size of a grain of salt. Each cell in the tissue gets tagged with a unique “molecular barcode” that represents the microwell it’s contained in, much like a zip code. The cells are then mixed up and assigned a second barcode to ensure that each cell within a given square can be individually identified, similar to a street address within a zip code. Finally, the genetic information in the form of RNA from each cell is analyzed. Once the results are obtained, both barcodes tell the researchers exactly where in the tissue it came from.

The team found that some cell types located near the liver tumor were not evenly spaced out. They also found immune cells and specific types of stem cells clustered in certain regions of the tumor. Additionally, certain stem cells had different levels of some RNA molecules depending on how far they resided from the tumor.

The researchers aren’t entirely sure what this pattern means, but they believe that it’s possible that signals generated by or near the tumor affect what nearby cells do.

In a press release, Alex Marson, M.D., Ph.D., a senior author of the study, elaborates on what the XYZeq technology could mean for disease modeling.

“I think we’re actually taking a step toward this being the way tissues are analyzed to diagnose, characterize, or study disease; this is the pathology of the future.”

The full results of the study were published in Science Advances.

CIRM funded stem cell therapy could one day help stroke and dementia patients

Image Description: Microscope images showing brain tissue that has been damaged by white matter stroke (left) and then repaired by the new glial cell therapy (right). Myelin (seen in red), is a substance that protects the connections between neurons and is lost due to white matter stroke. As seen at right, the glial cell therapy (green) restores lost myelin and improves connections in the brain. | Credit: UCLA Broad Stem Cell Research Center/Science Translational Medicine

Dementia is a general term that describes problems with memory, attention, communication, and physical coordination. One of the major causes of dementia is white matter strokes, which occurs when multiple strokes (i.e. a lack of blood supply to the brain) gradually damages the connecting areas of the brain (i.e. white matter).

Currently, there are no therapies capable of stopping the progression of white matter strokes or enhancing the brain’s limited ability to repair itself after they occur.

However, a CIRM-funded study ($2.09 million) conducted by S. Thomas Carmichael, M.D., Ph.D. and his team at UCLA showed that a one-time injection of an experimental stem cell therapy can repair brain damage and improve memory function in mice with conditions that mimic human strokes and dementia.

The therapy consists of glial cells, which are a special type of cell present in the central nervous system that surround and protect neurons. The glial cells are derived from induced pluripotent stem cells (iPSCS), stem cells that are derived from skin or blood cells through the process of reprogramming and have the ability to become virtually any type of cell.

Dr. Carmichael and his team injected the newly developed glial cells into the brains of mice that had damage similar to humans in the early to middle stages of dementia. The team found that the cell therapy traveled to the damaged areas of the brain and secreted chemicals that stimulated the brain’s own stem cells to start repairing the damage. This not only limited the progression of damage, but also enhanced the formation of new neural connections and increased the production of myelin, a fatty substance that covers and protects neurons.

In a press release from UCLA, Francesca Bosetti, Ph.D., Pharm.D., Program Director at the National Institute of Neurological Disorders and Strokes, was optimistic about what these findings could mean for patients with strokes or dementia.

“These preliminary results suggest that glial cell-based therapies may one day help combat the white matter damage that many stroke and vascular dementia patients suffer every year.”

Another interesting finding from this study is that even if the injected cells were eliminated a few months after they had been transplanted, the mice’s recovery was unaffected. The researchers believe that this indicates that the therapy primarily serves as a way to stimulate the brain’s own repair process.

In the same press release, Dr. Carmichael elaborates on this concept.

“Because the cell therapy is not directly repairing the brain, you don’t need to rely on the transplanted cells to persist in order for the treatment to be successful.”

The team is now conducting the additional studies necessary to apply to the Food and Drug Administration (FDA) for permission to test the therapy in a clinical trial in humans. If the therapy is shown to be safe and effective through clinical trials in humans, the team envisions that it could be used at hospitals as a one-time treatment for people with early signs of white matter stroke.

The full results of this study were published in Science Translational Medicine.

CIRM Board Approves Clinical Trials for Blood Cancer and Pediatric Brain Tumors

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $14.4 million for two new clinical trials for blood cancer and pediatric brain tumors.

These awards bring the total number of CIRM-funded clinical trials to 70. 

$6.0 million was awarded to Immune-Onc Therapeutics to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML), both of which are types of blood cancer. AML affects approximately 20,000 people in the United States each year and has a 5-year survival rate of about 25 percent. Anywhere from 15-30 percent of CMML cases eventually progress into AML.

Paul Woodard, M.D. and his team will treat AML and CMML patients with an antibody therapy called IO-202 that targets leukemic stem cells.  The antibody works by blocking a signal named LILRB4 whose expression is connected with decreased rates of survival in AML patients.  The goal is to attain complete cancer remissions and prolonged survival.

$8.4 million was also awarded to City of Hope to conduct a clinical trial for children with malignant brain tumors.  Brain tumors are the most common solid tumor of childhood, with roughly 5,000 new diagnoses per year in the United States.

Leo D. Wang, M.D., Ph.D. and his team will treat pediatric patients with aggressive brain tumors using chimeric antigen receptor (CAR) T cell therapy.  The CAR T therapy involves obtaining a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them so that they are able to identify and destroy the brain tumors.  The aim of this approach is to improve patient outcome.

“Funding the most promising therapies for aggressive blood cancer and brain tumors has always aligned with CIRM’s mission,” says Maria T. Millan, M.D., President and CEO of CIRM.  “We are excited to fund these trials as the first of many near-term and future stem cell- and regenerative medicine-based approaches that CIRM will be able to support with bond funds under Proposition 14”.

Positive results for patients enrolled in CIRM-funded trial of a rare pediatric disease

Leukocyte Adhesion Deficiency-I (LAD-I) is a rare pediatric disease that prevents patients from combating infections. This leads to recurring bacterial and fungal infections that respond poorly to antibiotics, require frequent hospitalizations, and can be fatal. It is caused by a mutation in a specific gene that causes low levels of a protein called CD18. The low levels of CD18 affect the immune system’s ability to work efficiently and reduces the body’s ability to combat infections.

Rocket Pharmaceuticals is conducting a CIRM-funded ($6.56 M) clinical trial that is testing a treatment that uses a gene therapy called RP-L201. The therapy uses a patient’s own blood stem cells and inserts a corrected version of the mutated gene.  These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections. Previous studies have indicated that an increase in CD18 expression to 4-10 percent is associated with survival into adulthood. 

Rocket presented promising results from four patients enrolled in the trial at the Clinical Immunology Society 2021 Annual Meeting.

Patient 1001 was 9 years-of-age at enrollment and had been followed for 18-months after treatment. Patient 1004 was 3 years-of-age at enrollment and had been followed for 9-months. Patients 2006 and 2005 were 7 months- and 2 years-of-age at enrollment and had been followed for 3-months.

Key findings from trial include the following:

  • RP-L201 was well tolerated and no safety issues reported with infusion or treatment.
  • Patient 1001 demonstrated CD18 expression of about 40 percent and resolution of skin lesions with no new lesions reported 18-months post-treatment.
  • Patient 1004 demonstrated CD18 expression of about 28 percent 9-months post-treatment.
  • Patient 2006 demonstrated CD18 expression of about 70 percent 3-months post-treatment.
  • Patient 2005 demonstrated CD18 expression of about 51 percent 3-months post-treatment.

In a news release, Jonathan Schwartz, M.D., Chief Medical Officer and Senior Vice President of Rocket expressed optimism for these findings.

“Today’s positive updates on our LAD-I program add to the growing body of encouraging evidence that RP-L201 may provide durable clinical benefit for patients with severe LAD-I who face recurrent, life-threatening infections from birth.”

To access the poster used for this presentation, visit Rocket’s website linked here.

Saying thanks and farewell to a friend

Tom Howing

In this job you get to meet a lot of remarkable people, none more so than the patients who volunteer to take part in what are giant experiments. They are courageous pioneers, willing to be among the first people to ever try a new therapy, knowing that it may not help them and, potentially, might even harm them.

Tom Howing was one such person. I got to know Tom when we were putting together our 2017 Annual Report. Back in 2015 Tom was diagnosed with Stage 4 cancer that had spread throughout his body. He underwent surgery and chemotherapy. That worked for a while, but then the cancer returned. So, Tom had more surgery and chemotherapy. Again, it worked for a while but when the cancer returned again Tom was running out of options.

That’s when he learned about a clinical trial with a company called Forty Seven Inc. that was testing a new anti-cancer therapy that CIRM was supporting. Tom says he didn’t hesitate.

“When I was diagnosed with cancer I knew I had battle ahead of me. After the cancer came back again they recommended I try this CD47 clinical trial. I said absolutely, let’s give it a spin. I guess one is always a bit concerned whenever you put the adjective “experimental” in front of anything. But I’ve always been a very optimistic and positive person and have great trust and faith in my caregivers.”

Optimistic and positive are great ways to describe Tom. Happily, his optimism was rewarded. The therapy worked.

“Scans and blood tests came back showing that the cancer appears to be held in check. My energy level is fantastic. The treatment that I had is so much less aggressive than chemo, my quality of life is just outstanding.”

But after a year or so Tom had to drop out of the trial. He tried other therapies and they kept the cancer at bay. For a while. But it kept coming back. And eventually Tom ran out of options. And last week, he ran out of time.

Tom was a truly fine man. He was kind, caring, funny, gracious and always grateful for what he had. He talked often about his family and how the stem cell therapy helped him spend not just more time with them, but quality time.

He knew when he signed up for the therapy that there were no guarantees, but he wanted to try, saying that even if it didn’t help him that the researchers might learn something to help others down the line.

“The most important thing I would say is, I want people to know there is always hope and to stay positive.”

Tom ultimately lost his battle with cancer. But he never lost his spirit, his delight in his family and his desire to keep going as long as he could. In typical Tom fashion he preferred to put his concerns aside and cheer others along.

“To all those people who are putting in all the hours at the bench and microscope, it’s important for them to know that they are making a huge impact on the lives of real people and they should celebrate it and revel in it and take great pride in it.”

We consider ourselves fortunate to have known Tom and to have been with him on part of his journey. He touched our lives, as he touched the lives of so many others. Our thoughts and wishes go out to his family and friends. He will be remembered, because we never forget our friends.

A few years ago Tom came and talked to the CIRM Board. Here is the video of that event.

Stem cell therapy for diabetic foot ulcers shows promise in new study

For individuals with diabetes, the body’s inability to properly control blood sugar levels can lead to a wide range of other problems as time passes. One major issue is a diabetic foot ulcer (DFU), an open sore or wound that is commonly located on the bottom of the foot and caused by poor blood circulation and nerve damage. It occurs in approximately 15% of individuals with diabetes and in severe cases can lead to foot or leg amputation. Unfortunately, there is usually no effective form of treatment for this condition.

However, results from several studies authorized by the Ministry of Health of Nicaragua showed that using a stem cell therapy to treat patients with DFUs was safe and could be beneficial to patients.

The first results in a pilot study after an 18-month period demonstrated safety of the therapy and complete wound healing by nine months. After the six-year mark, five of the initial 10 subjects still demonstrated persistence of clinical benefits. It should be noted that five had passed away due to cardiac and other non-study-related causes.

In another study, the team wanted to determine the safety and efficacy of the stem cell therapy to treat non-healing DFUs greater than 3 centimeters in diameter.

For this clinical trial, 63 people from 35 to 70 years old with Type 2 diabetes and chronic DFU, all of whom were amputation candidates, were treated with a mixture of various types of stem cells obtained from the patient’s own fat tissue. The stem cell therapy was injected directly into the DFU with the hopes of restoring damaged blood vessels and promoting blood circulation and healing.

Patients were seen six months post treatment to evaluate ulcer closure, with 51 patients achieving 100 percent DFU closure and eight having greater than 75 percent. Only three required early amputations and one patient died. At 12 months post treatment, 50 patients had 100 percent DFU healing, while four had greater than 85 percent healing.

In a news release, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine, expressed interest in evaluating this stem cell therapy and results further.

“This work should be reviewed as it demonstrates the possibility of a novel cell injection therapy that can alleviate pain and infection, accelerate wound healing, and possibly avoid amputation.”

The full results of the recent study were published in Stem Cells Translational Medicine.

CIRM funding helps improve immune cell therapy to combat HIV

Image description: T cell infected with HIV.
Image Credit: National Institute of Allergy and Infectious Diseases (NIAID)

In June of last year we wrote about how Dr. Scott Kitchen and his team at UCLA are engineering blood forming stem cells in order to fight HIV, a potentially deadly virus that attacks the immune system and can worsen into AIDS if left untreated. HIV causes havoc in the body by attacking T cells, a vital part of the body’s immune system that helps fight off infections and diseases.

Dr. Kitchen’s approach uses what is called Chimeric Antigen Receptor (CAR) T gene therapy. This is a type of immune therapy that involves genetically modifying the body’s own blood forming stem cells to create T cells that have the ability to fight HIV. These newly formed immune cells have the potential to not only destroy HIV-infected cells but to create “memory cells” that could provide lifelong protection from HIV infection.

Flash forward to April of this year and the results of the CIRM funded study ($1.7M) have been published in PLOS Pathogens.

Unfortunately, although the previously designed CAR T gene therapy was still able to create HIV fighting immune cells, the way the CAR T gene therapy was designed still had the potential to allow for HIV infection.

For this new study, the team modified the CAR T gene therapy such that the cells would be resistant to infection and allow for a more efficient and longer-lasting cell response against HIV than before.

While the previous approach allowed for the continuous production of new HIV-fighting T cells that persisted for more than two years, these cells are inactivated until they come across the HIV virus. The improved CAR T gene therapy engineers the body’s immune response to HIV rather than waiting for the virus to induce a response. This is similar in concept to how a vaccine prepares the immune system to respond against a virus. The new approach also creates a significant number of “memory” T cells that are capable of quickly responding to reactivated HIV. 

The hope is that these findings can influence the development of T cells that are able carry “immune system” memory with the ability to recognize and kill virus-infected or cancerous cells. 

To date, CIRM has also funded four separate clinical trials related to the treatment of HIV/AIDS totaling over $31 million.

Three UC’s Join Forces to Launch CRISPR Clinical Trial Targeting Sickle Cell Disease

Sickle shaped red blood cells

The University of California, San Francisco (UCSF), in collaboration with UC Berkeley (UCB) and UC Los Angeles (UCLA), have been given permission by the US Food and Drug Administration (FDA) to launch a first-in-human clinical trial using CRISPR technology as a gene-editing technique to cure Sickle Cell Disease.

This research has been funded by CIRM from the early stages and, in a co-funding partnership with theNational Heart, Lung, and Blood Institute under the Cure Sickle Cell initiatve, CIRM supported the work that allowed this program to gain FDA permission to proceed into clinical trials.    

Sickle Cell Disease is a blood disorder that affects around 100,000 people, mostly Black and Latinx people in the US. It is caused by a single genetic mutation that results in the production of “sickle” shaped red blood cells. Normal red blood cells are round and smooth and flow easily through blood vessels. But the sickle-shaped ones are rigid and brittle and clump together, clogging vessels and causing painful crisis episodes, recurrent hospitalization, multi-organ damage and mini-strokes.    

The three UC’s have combined their respective expertise to bring this program forward.

The CRISPR-Cas9 technology was developed by UC Berkeley’s Nobel laureate Jennifer Doudna, PhD. UCLA is a collaborating site, with expertise in genetic analysis and cell manufacturing and UCSF Benioff Children’s Hospital Oakland is the lead clinical center, leveraging its renowned expertise in cord blood and marrow transplantation and in gene therapy for sickle cell disease.

The approach involves retrieving blood stem cells from the patient and, using a technique involving electrical pulses, these cells are treated to correct the mutation using CRISPR technology. The corrected cells will then be transplanted back into the patient.

Dr. Mark Walters

In a news release, UCSF’s Dr. Mark Walters, the principal investigator of the project, says using this new gene-editing approach could be a game-changer. “This therapy has the potential to transform sickle cell disease care by producing an accessible, curative treatment that is safer than the current therapy of stem cell transplant from a healthy bone marrow donor. If this is successfully applied in young patients, it has the potential to prevent irreversible complications of the disease. Based on our experience with bone marrow transplants, we predict that correcting 20% of the genes should be sufficient to out-compete the native sickle cells and have a strong clinical benefit.”

Dr. Maria T. Millan, President & CEO of CIRM, said this collaborative approach can be a model for tackling other diseases. “When we entered into our partnership with the NHLBI we hoped that combining our resources and expertise could accelerate the development of cell and gene therapies for SCD. And now to see these three UC institutions collaborating on bringing this therapy to patients is truly exciting and highlights how working together we can achieve far more than just operating individually.”

The 4-year study will include six adults and three adolescents with severe sickle cell disease. It is planned to begin this summer in Oakland and Los Angeles.

The three UCs combined to produce a video to accompany news about the trial. Here it is:

Prime Time for Rocket

Rocket Pharmaceuticals, a company that specializes in developing genetic therapies for rare childhood disorders, just got a big boost from the European Medicines Agency (EMA). They were given a Priority Medicines (PRIME) designation for their therapy for Leukocyte Adhesion Deficiency-1 (LAD-1).

CIRM is funding ($6.56 million) Rocket’s clinical trial for LAD-I, an immune disorder that leaves patients vulnerable to repeated infections that often results in death within the first two years of life. The therapy involves taking some of the child’s own blood stem cells and, in the lab, correcting the mutation that causes LAD-I, then returning those cells to the patient. Hopefully those blood stem cells then create a new, healthy blood supply and repair the immune system.

The therapy, called RP-L201, is already showing promise in the clinical trial, hence the PRIME designation. The program was set up to help speed up development and evaluation of therapies that could help patients who have limited treatment options. Getting a PRIME designation means it is considered a priority by EMA and could reach patients sooner.

In the US, Rocket has won similar recognition from the Food and Drug Administration (FDA) and has been granted Regenerative Medicine Advanced Therapy (RMAT), Rare Pediatric Disease, and Fast Track designations.

In a news release Kinnari Patel, President and Chief Operating Officer of Rocket, said the designation showed that regulators understand the urgent need to develop a therapy for patients with LAD-1. “More than half of LAD-I patients suffer with a severe variant in which mortality occurs in up to 75% of young children who don’t receive a successful bone marrow transplant by the age of two. Securing all possible accelerated designations will enable us to collaborate with both the FDA and EMA to speed the development and delivery of a potential treatment for these patients.  We look forward to sharing initial Phase 2 data from our potentially registration-enabling LAD-I trial in the second quarter of 2021.”

That trial has now completed enrolling patients (nine altogether) but their treatments are not yet complete. LAD-1 patients with severe disease have low levels of a key protein called CD18, usually less than 2%. Of the first three patients treated in this trial CD18 levels are all higher than the 4-10% threshold considered necessary for these children to survive into adulthood. Another encouraging sign is that there were no serious side effects from the therapy.

Obviously there is still a long way to go before we know if this therapy really works, but the PRIME designation – along with the similar ones in the US – are recognition that this is a very promising start.