CIRM funded study uses drug development in a dish for treatment of heart arrhythmias

Image Credit: Center for Disease Control and Prevention (CDC)

Cardiac (heart) arrhythmias occur when electrical impulses that coordinate your heartbeats don’t work properly, causing your heart to beat too fast, too slow, or in an irregular manner. In the U.S. alone, almost one million individuals are hospitalized every year for heart arrhythmias. Close to 300,000 individuals die of sudden arrhythmic death syndrome every year, which occurs when there is a sudden loss of blood flow resulting from the failure of the heart to pump effectively. Unfortunately, drugs to treat arrhythmias have liabilities and several drugs have been pulled from the market due to serious side effects. Mexiletine is one potential drug for heart arrhythmias that has liabilities and potential side effects.

That is why a CIRM funded study ($6.3 million) conducted by John Cashman, Ph.D. at the Human BioMolecular Research Institute in San Diego looked at re-engineering mexiletine in a way that the drug could still produce a desired result and not be as toxic.

The study used induced pluripotent stem cells (iPSCs), a type of stem cell “reprogrammed” from the skin or blood of patients that can be used to make virtually any kind of cell. iPSCs obtained for the study were from a healthy patient and from one with a type of heart arrhythmia. The healthy and arrhythmia iPSCs were then converted into cardiomyocytes, a type of cell that makes up the heart muscle.

By using their newly created healthy cardiomyocytes and those with the arrhythmia defect, Cashman and his team were able to carry out drug development in a dish. This enabled them to attempt to lessen drug toxicity while still potentially treating heart arrhythmias. The team was able to modify mexiletine such that is was less toxic and found that it could potentially decrease a patient’s risk of developing ventricular tachycardia (a fast, abnormal heart rate) and ventricular fibrillation (an abnormal heart rhythm), both of which are types of heart arrhythmias.

“The new compounds may lead to treatment applications in a whole host of cardiovascular conditions that may prove efficacious in clinical trials,” said Cashman in a press release. “As antiarrhythmic drug candidate drug development progresses, we expect the new analogs to be less toxic than current therapeutics for arrhythmia in congenital heart disease, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

The team hopes that their study can pave the way for future research in which cells in a dish can be used to lessen the toxicity of a potential drug candidate while still producing a desired result for different diseases and conditions.

The full study was published in ACS Publications.

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.

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.

CIRM funding helps identify potential COVID-19 treatment

The steps of the virus growth cycle that can be targeted with therapies: The virus enters a host cell (1), the virus’s genetic instructions are released, taking over cellular machinery (2), the virus is replicated within the cell (3) and copies of the virus exit the cell in search of new host cells to infect (4). Drugs like berzosertib might disrupt steps 2 and 3.  Image credit: Marc Roseboro/California NanoSytems Institute at UCLA

During the global pandemic, many researchers have responded to the needs of patients severely afflicted with COVID-19 by repurposing existing therapies being developed to treat patients.  CIRM responded immediately to the pandemic and to researchers wanting to help by providing $5 million in emergency funding for COVID-19 related projects. 

One of these grants ($349,999), awarded to Dr. Vaithilingaraja Arumugaswami at UCLA, has aided a study that has singled out a compound that shows promise for treating SARS-CoV-2, the virus that causes COVID-19.

In the spirit of banding together to help patients severely affected by COVID-19, the project was a collaboration among scientists from UCLA and other universities in California, Delaware and Germany, as well as a German pharmaceutical company.

The compound is named berzosertib and is licensed by the company Merck KGaA in Darmstadt, Germany.  Prior to the pandemic, it was developed for potential use, in combination with chemotherapy, as a possible treatment for small-cell lung cancer, ovarian cancer, and other types of solid tumors.

The team screened 430 drugs from among the approximately 200,000 compounds in CNSI’s Molecular Screening Shared Resource libraries before zeroing in on berzosertib as the most promising candidate.  They limited their search to compounds that either had been approved, or are already in the process of being evaluated, for safety in humans.

In a press release from UCLA, Dr. Arumugawami explains the rationale behind screening a potential drug candidate.

“That way, the compounds have cleared the first regulatory hurdle and could be deployed for further clinical trials on COVID-19 faster than drugs that have not been tested in humans.”

The researchers, led by Dr. Arumugaswami and Dr. Robert Damoiseaux from UCLA, conducted a series of experiments using different cell types in lab dishes to look at how effective the compound was at blocking SARS-CoV-2 from replicating.  Unlike other approaches which attack the virus directly, targeting replication could help better address the ability of the virus to mutate. 

For this study, the team used cells from the kidney, heart and lungs, all of which are organs that the virus is known to attack. The researchers pretreated cells with berzosertib, exposed the cells to SARS-CoV-2, allowed 48 hours for infection to set in, and then evaluated the results.

The team found that the compound consistently stalled SARS-CoV-2 replication without damaging the cells. The scientists also tested the drug against SARS and MERS, both of which are other types of coronaviruses that triggered deadly outbreaks earlier in the 2000s. They found that it was effective in stopping the replication of those viruses as well.

In the same press release from UCLA, Dr. Damoiseaux expressed optimism for what these findings could mean as a potential treatment.

“This is a chance to actually find a drug that might be broader in spectrum, which could also help fight coronaviruses that are yet to come.”

The next steps for this research would be to explore the mechanism through which the compound blocks coronavirus replication.  Understanding this and conducting preclinical studies are both necessary before the compound could be tested in clinical trials for COVID-19.

The full results of this study were published in Cell Reports.

The study’s co-corresponding author is Ulrich Betz of Merck KGaA, Darmstadt, Germany; the company also provided partial funding and clinical-grade berzosertib for the research. Other co-authors are from UCLA, Cedars-Sinai Medical Center, UC Irvine, University of Delaware, the Leibniz Institute for Experimental Virology in Germany, Heidelberg University in Germany and Scripps Research Institute.

In addition to CIRM, the study was also funded by CNSI, the Broad Stem Cell Research Center, the David Geffen School of Medicine at UCLA, the National Eye Institute, and the Bill and Melinda Gates Foundation.

Newly designed “bioink” get us one step closer to 3D printed organs

3D bioprinted small airways made out of two cell types (blue and yellow) remain open over time.

3D printing technology has revolutionized the way we think about creating things with complex designs with the simple click of a button. The ability to be able to give a computer a specific set of instructions and hit “print” is appealing in this modern era of instant gratification and convenience. In the regenerative medicine field, there has been a specific interest in using this type of technology to create vital organs for transplants, something that would be extremely helpful to those anxiously waiting for a donor.

Researchers at Lund University in Sweden have gotten one step closer to making 3D organ printing a reality by designing a new type of “bioink” which allows small human-sized airways to be 3D-bioprinted using patient cells for the first time. For this project, the researchers focused on the lungs but the proof of concept could be applicable to other types of organs.

Like many other debilitating conditions, there is no cure for chronic lung disease and the only end-stage option for patients is lung transplantation. However, there are not enough donor lungs to meet clinical demand.

The researchers first designed a new type of “bioink”, which is a printable material made with cells. The “bioink” was made by combining materials made from seaweed, alginate, and an extracellular matrix made from lung tissue. The “bioink” is important because it supports the bioprinted material over several stages of its development towards tissue. The researchers used it to 3D-bioprint small human airways containing two types of cells found in human airways.

Blood vessel infiltration in the 3D bioprinted constructs.

The team then used a mouse model closely resembling the immunosuppression used in patients undergoing organ transplantation and transplanted the newly created cells inside the mice. What they found was remarkable in that the 3D-printed airways made from the new “bioink” were well-tolerated and supported new blood vessels.

Although more work needs to be done in order to perfect this technique, these results provide a pivotal step forward in one day making bioprinting organs a reality.

In a press release, Dr. Darcy Wagner, senior author of this study, expresses optimism about their findings.

“We hope that further technological improvements of available 3D printers and further ‘bioink’ advances will allow for bioprinting at a higher resolution in order to engineer larger tissues which could be used for transplantation in the future.”

The full results of this study were published in Advanced Materials.

Study shows reduction in brain injury after stroke patients were treated with their own stem cells

Illustration showing the mechanism of an ischemic stroke. In an ischemic stroke, blood supply to part of the brain is decreased, leading to dysfunction of that area of the brain. Here, a blood clot is the reason for restricted blood flow.

Stroke is the third leading cause of death and serious long-term disability and affects nearly 800,000 Americans a year, with someone in the U.S. suffering a stroke every 40 seconds. Roughly 87% of all strokes are ischemic strokes, meaning that a clot blocks blood flow to the brain. Unfortunately 90% of those who suffer an ischemic stroke also end up suffering from weakness or paralysis to one side of the body.

A study conducted by Muhammad Haque, Ph.D. and Sean Savitz, M.D. at The University of Texas Health Science Center at Houston (UTHealth) found that treating patients with stem cells from their own bone marrow could lead to a reduction in brain injury after a stroke caused by a blood clot.

For this study, there were 37 patients from ages 18 to 80. While all received the standard stroke treatment and rehabilitation follow-up, 17 patients whose strokes were the most severe received a bone marrow stem cell therapy. To measure any improvement, the UTHealth team used 3D brain imaging of the patients obtained from MRI scans. They used these images to compare changes in white matter of those treated with their own bone marrow stem cells to those who were not treated.

White matter is a specific type of tissue in the brain that is critical for motor function because it is responsible for carrying movement-related information to the spinal cord.

Three months after the stroke, the MRI scans of each patient showed the expected decrease after a stroke. However, scans taken 12 months after the stroke occurred showed an improvement on average in the 17 patients who received bone marrow cell therapy.

In a press release from UTHealth, Dr. Haque elaborates on what these results could mean for developing treamtents for stroke patients.

“We envision that future clinical trials might be directed toward identifying white matter protection or repair as an important mechanistic target of efficacy studies and potency assays for bone marrow cell therapies.”

The full results to this study were published in STEM CELLS Translational Medicine.