Dilated cardiomyopathy (DCM), a condition where the muscles of the heart are weak and can lead to heart failure, is considered rare in children. However, because the symptoms are not always easy to recognize the condition can go unnoticed for many years, and in severe cases can damage the heart irreparably. In that case the child’s only option is a heart transplant, and a lack of organ donors means that is not always available.
Now, new research out of Japan – published in the journal Science Translation Medicine – could lead the way to new treatments to help children avoid the need for a transplant.
In the study, researchers at Okayama University used heart stem cells called cardiosphere-derived cells (CDCs) to try and repair the damage caused by DCM.
In a news release, lead researcher Professor Hidemasa Oh, says previous work has shown that because CDCs have the ability to turn into heart tissue they have the potential of reversing damage, but it’s not clear if this would work in children.
“I have been working on cardiac regeneration therapy since 2001. In this study, my team and I assessed the safety and efficacy of using CDCs to treat DCM in children.”
Tests in animal models with DCM showed that the CDCs resulted in a thickening of the heart muscle leading to increased blood flow around the body. This increased blood supply helped repair damaged tissue. Based on this trial the researcher determined what might be a suitable dose of CDCs for children with DCM and were granted permission to carry out a Phase 1 clinical trial.
Five young patients were treated and the results were cautiously encouraging. After a year none of the patients had experienced any severe side effects, but all had indications of improved heart function.
The study also gave the researchers some strong clues as to how the therapy seem to work. They found that when the CDCs were transplanted into the patient they secreted exosomes, which play an important role in cells communicating with one another. These exosomes then helped create a series of actions within the body; they blocked further damage to the heart tissue and they also helped kickstart the repair process.
The Okayama team are now hoping to carry out a Phase 2 clinical trial with more patients. Ultimately, they hope to be able to see if this approach could help prevent the need for a heart transplant in children, and even adults.
When someone has a stroke, the blood flow to the brain is blocked. This kills some nerve cells and injures others. The damaged nerve cells are unable to communicate with other cells, which often results in people having impaired speech or movement.
While ischemic and hemorrhagic strokes affect large blood vessels and usually produce recognizable symptoms there’s another kind of stroke that is virtually silent. A ‘white’ stroke occurs in blood vessels so tiny that the impact may not be noticed. But over time that damage can accumulate and lead to a form of dementia and even speed up the progression of Alzheimer’s disease.
Now Dr. Tom Carmichael and his team at the David Geffen School of Medicine at UCLA have developed a potential treatment for this, using stem cells that may help repair the damage caused by a white stroke. This was part of a CIRM-funded study (DISC2-12169 – $250,000).
Instead of trying to directly repair the damaged neurons, the brain nerve cells affected by a stroke, they are creating support cells called astrocytes, to help stimulate the body’s own repair mechanisms.
In a news release, Dr. Irene Llorente, the study’s first author, says these astrocytes play an important role in the brain.
“These cells accomplish many tasks in repairing the brain. We wanted to replace the cells that we knew were lost, but along the way, we learned that these astrocytes also help in other ways.”
The researchers took skin tissue and, using the iPSC method (which enables researchers to turn cells into any other kind of cell in the body) turned it into astrocytes. They then boosted the ability of these astrocytes to produce chemical signals that can stimulate healing among the cells damaged by the stroke.
These astrocytes were then not only able to help repair some of the damaged neurons, enabling them to once again communicate with other neurons, but they also helped another kind of brain cell called oligodendrocyte progenitor cells or OPCs. These cells help make a protective sheath around axons, which transmit electrical signals between brain cells. The new astrocytes stimulated the OPCs into repairing the protective sheath around the axons.
Mice who had these astrocytes implanted in them showed improved memory and motor skills within four months of the treatment.
And now the team have taken this approach one step further. They have developed a method of growing these astrocytes in large amounts, at very high quality, in a relatively short time. The importance of that is it means they can produce the number of cells needed to treat a person.
“We can produce the astrocytes in 35 days,” Llorente says. “This process allows rapid, efficient, reliable and clinically viable production of our therapeutic product.”
The next step is to chat with the Food and Drug Administration (FDA) to see what else they’ll need to do to show they are ready for a clinical trial.
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.
The US Food and Drug Administration (FDA) has granted Investigational New Drug (IND) permission enabling Graphite Bio to test the investigational, potentially revolutionary gene editing therapy GPH101 developed under the supervision of Matthew Porteus, MD, PhD, in a clinical trial for people with sickle cell disease (SCD).
The California Institute for Regenerative Medicine (CIRM) has been supporting this project with a $5.2 million grant, enabling Dr. Porteus and his team at the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University to conduct the preclinical manufacturing and safety studies required by the FDA.
“We congratulate the Graphite Bio team for obtaining the IND, a critical step in bringing the GPH101 gene therapy forward for Sickle Cell Disease,” says Dr. Maria T. Millan, CIRM’s President & CEO. “CIRM is committed to the national Cure Sickle Cell initiative and are delighted that this technology, the product of CIRM funded research conducted by Dr. Porteus at Stanford, is progressing to the next stage of development”
Sickle cell disease is caused by a genetic mutation that turns normally smooth, round red blood cells into rigid, sickle shaped cells. Those cells clump together, clogging up blood vessels, causing intense pain, damaging organs and increasing the risk of strokes and premature death. There are treatments that help control the damage, but the only cure is a bone marrow stem cell transplant, which can only happen if the patient has a stem cell donor (usually a close relative) who has matching bone marrow.
The investigational therapy GPH101 harnesses the power of CRISPR and natural DNA repair mechanisms to cut out the single mutation in the sickle globin gene and paste in the correct “code.” Correction of this mutation would reverse the defect and result in healthy non-sickling red blood cells.
CEDAR, a Phase 1/2, multi-center, open-label clinical study is designed to evaluate the safety, preliminary efficacy and pharmacodynamics of GPH101 in adult and adolescent patients with severe SCD.
For patient advocate Nancy Rene, the news is personal: “It’s always exciting to hear about the progress being made in sickle cell research. If successful it will mean that my grandson, and especially other young adults, can look forward to a life free of pain and organ damage. They can actually begin to plan their lives, thinking about careers and families. I want to thank Dr. Porteus and all of the scientists who are working so hard for people with sickle cell disease. This is wonderful news.”
CIRM has funded four clinical trials for Sickle Cell Disease using different approaches and has a unique partnership with the National Heart, Lung and Blood Institutes under the NIH “Cure Sickle Cell” initiative.
Yesterday the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $9.28 million to Dr. Saul Priceman at City of Hope to conduct a clinical trial for the treatment of breast cancer related brain metastases, which are tumors in the brain that have spread from the original site of the breast cancer.
This award brings the total number of CIRM-funded clinical trials to 56.
Breast cancer is the second-most common cancer in women, both in the United States (US) and worldwide. It is estimated that over 260,000 women in the US will be diagnosed with breast cancer in 2019 and 1 out of 8 women in the US will get breast cancer at some point during her lifetime. Some types of breast cancer have a high likelihood of metastasizing to the brain. When that happens, there are few treatment options, leading to a poor prognosis and poor quality of life.
Dr. Priceman’s clinical trial is testing a therapy to treat brain metastases that came from breast cancers expressing high levels of a protein called HER2. The therapy consists of a genetically-modified version of the patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T cells are modified with a protein called a chimeric antigen receptor (CAR) that recognizes the tumor protein HER2. These modified T cells (CAR-T cells) are then infused into the patient’s brain where they are expected to detect and destroy the HER2-expressing tumors in the brain.
CIRM has also funded the earlier work related to this study, which was critical in preparing the therapy for Food and Drug Administration (FDA) approval for permission to start a clinical trial in people.
“When a patient is told that their cancer has metastasized to other areas of the body, it can be devastating news,” says Maria T. Millan, M.D., the President and CEO of CIRM. “There are few options for patients with breast cancer brain metastases. Standard of care treatments, which include brain irradiation and chemotherapy, have associated neurotoxicity and do little to improve survival, which is typically no more than a few months. CAR-T cell therapy is an exciting and promising approach that now offers us a more targeted approach to address this condition.”
The CIRM Board also approved investing $19.7 million in four awards in the Translational Research program. The goal of this program is to help promising projects complete the testing needed to begin talking to the US Food and Drug Administration (FDA) about holding a clinical trial.
Dr. Mark Tuszynski at the University of California San Diego (UCSD) was awarded $6.23 million to develop a therapy for spinal cord injury (SCI). Dr. Tuszynski will use human embryonic stem cells (hESCs) to create neural stem cells (NSCs) which will then be grafted at the injury site. In preclinical studies, the NSCs have been shown to help create a kind of relay at the injury site, restoring communication between the brain and spinal cord and re-establishing muscle control and movement.
Dr. Mark Humayun at the University of Southern California (USC) was awarded $3.73 million to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD), the leading cause of vision loss in the US.
The approach that Dr. Humayun is developing will use a biologic product produced by human embryonic stem cells (hESCs). This material will be injected into the eye of patients with early development of dry AMD, supporting the survival of photoreceptors in the affected retina, the kind of cells damaged by the disease.
The TRAN1 awards went to:
Stay tuned for our next blog which will dive into each of these awards in much more detail.
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both types of blood cancers that can be difficult to treat. CIRM is fundingForty Seven, Inc. to conduct a clinical trial to treat patients with these blood cancers with an antibody called 5F9. CIRM has also given multiple awards prior to the clinical trial to help in developing the antibody.
Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, which are white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. The antibody works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.
In a press release, Forty Seven, Inc. announced early clinical results from their CIRM funded trial using the antibody to treat patients with AML and MDS. Some patients received just the antibody while others received the antibody in combination with azacitidine, a chemotherapy drug used to treat these cancers.
Here is a synopsis of the trial:
35 patients treated in a Phase 1 clinical trial have been evaluated for a response assessment to-date.
10 of these have MDS or AML and only received the 5F9 antibody.
11 of these have higher-risk MDS and received the 5F9 antibody along with the chemotherapy drug azacitidine.
14 of these have untreated AML and received the 5F9 antibody along with the chemotherapy drug azacitidine.
For the 11 patients with higher-risk MDS treated with the antibody and chemotherapy, they found that:
All 11 patients achieved an objective response rate (ORR),meaning that there was a reduction in tumor burden of a predefined amount.
Six of these patients achieved a complete response (CR), indicatinga disappearance of all signs of cancer in response to treatment.
For the 14 patients with untreated AML treated with the antibody and chemotherapy, they found that:
Nine of these patients achieved an ORR.
Five of theseninepatients achieved a CR.
Two of these nine patientsachieved a morphologic leukemia-free state (MLFS), indicating the disappearance of all cells with formal and structural characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
The remaining five patients achieved stable disease (SD), meaning that the tumor is neither growing nor shrinking.
The results also showed that:
There was no evidence of increased toxicities when the antibody was used alongside the chemotherapy drugs, demonstrating tolerance and safety of the treatment.
No responding MDS or AML patient has relapsed or progressed on the antibody in combination with chemotherapy, with a median follow-up of 3.8 months.
The median time to response was rapid at 1.9 months.
Several patients have experienced deepening responses over time resulting in complete remissions.
Based on the favorable results observed in this clinical trial to-date, expansion cohorts have been initiated, meaning that additional patients will be enrolled in a phase I trial. This will include patients with both higher-risk MDS and untreated AML as well as using the antibody in combination with chemotherapy.
In the press release, Dr. David Sallman, an investigator in the clinical trial, is quoted as saying,
“These new data for 5F9 show encouraging clinical activity in a broad population of patients with MDS and AML, who may be unfit for existing therapeutic options or at higher-risk for developing rapidly-advancing disease. Despite an evolving treatment landscape, physicians continue to seek new therapies for MDS and AML that can be used safely in combination with standard-of-care to help patients more rapidly achieve durable responses. To that end, I am excited to see meaningful clinical activity in a majority of patients treated with 5F9 in combination with azacitidine, with a median time to response of under two months and no relapses or progressions among responding patients.”
Our immune system is an important and essential part of everyday life. It is crucial for fighting off colds and, with the help of vaccinations, gives us immunity to potentially lethal diseases. Unfortunately, for some infants, this innate bodily defense mechanism is not present or is severely lacking in function.
This condition is known as severe combined immunodeficiency (SCID), commonly nicknamed “bubble baby” disease because of the sterile plastic bubble these infants used to be placed in to prevent exposure to bacteria, viruses, and fungi that can cause infection. There are several forms of SCID, one of which involves a single genetic mutation on the X chromosome and is known as SCID-X1
Many infants with SCID-X1 develop chronic diarrhea, a fungal infection called thrush, and skin rashes. Additionally, these infants grow slowly in comparison to other children. Without treatment, many infants with SCID-X1 do not live beyond infancy.
SCID-X1 occurs almost predominantly in males since they only carry one X chromosome, with at least 1 in 50,000 baby boys born with this condition. Since females carry two X chromosomes, one inherited from each parent, they are unlikely to inherit two X chromosomes with the mutation present since it would require the father to have SCID-X1.
What if there was a way to address this condition by correcting the single gene mutation? Dr. Matthew Porteus at Stanford University is leading a study that has developed an approach to treat SCID-X1 that utilizes this concept.
By using CRISPR-Cas9 technology, which we have discussed in detail in a previous blog post, it is possible to delete a problematic gene and insert a corrected gene. Dr. Porteus and his team are using CRISPR-Cas9 to edit blood stem cells, which give rise to immune cells, which are the foundation of the body’s defense mechanism. In a study published in Nature, Dr. Porteus and his team have demonstrated proof of concept of this approach in an animal model.
The Stanford team was able to take blood stem cells from six infants with SCID-X1 and corrected them with CRISPR-Cas9. These corrected stem cells were then introduced into mice modeled to have SCID-X1. It was found that these mice were not only able to make immune cells, but many of the edited stem cells maintained their ability to continuously create new blood cells.
In a press release, Dr. Mara Pavel-Dinu, a member of the research team, said:
“To our knowledge, it’s the first time that human SCID-X1 cells edited with CRISPR-Cas9 have been successfully used to make human immune cells in an animal model.”
CIRM has previously awarded Dr. Porteus with a preclinical development award aimed at developing gene correction therapy for blood stem cells for SCID-X1. In addition to this, CIRM has funded two other projects conducted by Dr. Porteus related to CRISPR-Cas9. One of these projects used CRISPR-Cas 9 to develop a treatment for chronic sinusitis due to cystic fibrosis and the second project used the technology to develop an approach for treating sickle cell disease.
CIRM has also funded four clinical trials related to SCID. Two of these trials are related to SCID-X1, one being conducted at St. Jude Children’s Research Hospital and the other at Stanford University. The third trial is related to a different form of SCID known as ADA-SCID and is being conducted at UCLA in partnership with Orchard Therapeutics. Finally, the last of the four trials is related to an additional form of SCID known as ART-SCID and is being conducted at UCSF.
Blood is the lifeline of the body. The continuous, unimpeded circulation of blood maintains oxygen flow throughout the body and enables us to carry out our everyday activities. Unfortunately, there are individuals whose own bodies are in a constant battle that prevents this from occurring seamlessly. They have something known as sickle cell disease (SCD), an inherited condition caused by a mutation in a single gene. Rather than producing normal, circular red blood cells, their bodies produce sickle shaped cells (hence the name) that can become lodged in blood vessels, preventing blood flow. The lack of blood flow can cause agonizing pain, known as crises, as well as strokes. Chronic crises can cause organ damage, which can eventually lead to organ failure. Additionally, since the misshapen cells don’t survive long in the body, people with SCD have a greater risk of being severely anemic and are more prone to infections. Monthly blood transfusions are often needed to help temporarily alleviate symptoms. Due to the debilitating nature of SCD, important aspects of everyday life such as employment and health insurance can be extremely challenging to find and maintain.
An estimated 100,000 people in the United States are living with SCD. Around the world, about 300,000 infants are born with the condition each year, a statistic that will increase to 400,000 by 2050 according to one study. Many people with SCD do not live past the age of 50. It is most prevalent in individuals with sub-Saharan African descent followed by people of Hispanic descent. Experts have stated that advances in treatment have been limited in part because SCD is concentrated in poorer minority communities.
Despite these grim statistics and prognosis, there is hope.
The New York Times and Boston Herald recently released featured articles that tell the personal stories of patients enrolled in a clinical trial conducted by bluebird bio. The trial uses gene therapy in combination with hematopoietic (blood) stem cells (HSCs) to give rise to normal red blood cells in SCD patients.
Here are the stories of these patients. To read the full New York Times article, click here. For the Boston Herald article, click here.
Emmanuel “Manny” Johnson was the very first patient in the SCD trial. He was motivated to participate in the trial not just for himself but for his younger brother Aiden Johnson, who was also born with SCD. Manny has a tattoo with Aiden’s name written inside a red sickle cell awareness ribbon.
In the article Manny is quoted as saying “It’s not only that we share the same blood disease, it’s like I have to do better for him.”
Since receiving the treatment, Manny’s SCD symptoms have disappeared.
For Brandon Williams of Chicago, the story of SCD is a very personal one. At just 21 years old, Brandon had suffered four strokes by the time he turned 18. His older sister, Britney Williams, died of sickle cell disease at the age of 22. Brandon was devastated and felt that his own life could end at any moment. He was then told about the SCD trial and decided to enroll. Following the treatment, his symptoms have vanished along with the pain and fear inflicted by the disease.
The NY Times piece also profiles Carmen Duncan, a 20 year old from Charleston, South Carolina. She had her spleen removed when she was just two years old as a result of complications form SCD. Duncan spent a large portion of her childhood in hospitals, coping with the pain in her arms and legs from blocked blood vessels. She enrolled in the SCD trial as well and she no longer has any signs of SCD. Duncan had aspirations to join the military but was unable to because of her condition. Now that she is symptom free, she plans to enlist.
ViaCyte, a company that CIRM has supported for many years, has announced international expansion of a clinical trial to test their therapeutic PEC-Direct product in patients with Type I Diabetes.
The first European patient in Brussels was implanted with the PEC-Direct product candidate that, in animal models, is able to form functional beta cells. Patients with Type I Diabetes are unable to control blood glucose levels because their immune system attacks insulin-producing beta cells, which are responsible for regulating blood sugar.
ViaCyte PEC-Direct product candidate
The hope is that PEC-Direct would eliminate the need for patients to take daily doses of insulin, the current treatment standard to prevent the side effects of high blood glucose levels, such as heart disease, kidney damage and nerve damage.
The PEC-Direct product is implanted under the skin. The progenitor cells inside it are designed to mature in to human pancreatic islet cells, including glucose-responsive insulin-secreting beta cells, following implant. These are the cells destroyed by Type 1 Diabetes
In this first phase of the clinical trial, patients are administered a subtherapeutic dose of the drug to ensure that that the implants are able to generate beta cells in the body. The next part of the trial will determine whether or not the formed beta cells are able to produce appropriate levels of insulin and modulate blood glucose levels. A sister trial is currently underway in North America as well. This work is a collaboration between ViaCyte and The Center for Beta Cell Therapy in Diabetes.
CIRM is proud to be a supporter of companies such as ViaCyte that are conducting groundbreaking research to make stem cell therapy an effective and realistic treatment option for many different diseases.
For years chemotherapy has been a mainstay in the war against cancer. While it can be very effective it can also come with some nasty side effects. Since chemo works by killing rapidly growing cells, it not only hits the cancer cells, but can also hit other rapidly growing cells too, including those in our hair roots, which is why many people undergoing chemo lose their hair.
So, the key to a truly effective anti-cancer therapy is one that does as much damage as possible to the cancer cells, and as little as possible to all the healthy cells in the body. A therapy being developed by Cellerant Therapeutics seems to have found that sweet spot in a new therapy targeting acute myeloid leukemia (AML).
AML starts in the bone marrow and quickly moves into the blood, where it can spread to other parts of the body. It is the second most common form of leukemia and claims around 10,000 lives in the US every year. Chemotherapy is the main weapon used against AML but it can also cause nausea, hair loss and other complications and in most cases has limited effectiveness because, over time, the leukemia cells get used to it.
In a study published in the journal Blood Advances, Cellerant researchers explain the limitations of existing treatments.
“The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy.”
Cellerant has developed a therapy called CLT030 which targets CLL1, a marker found on the surface of leukemia cells but not on normal blood stem cells. Preclinical studies in mice show CLT030 is able to zero in on this surface marker and attack the leukemia but do little damage to blood or other surrounding cells.
In a news release, Ram Mandalam, President and CEO of Cellerant, said this is encouraging news:
“AML remains a significant unmet medical need, and our therapy, CLT030, that can target leukemic stem cells precisely while minimally affecting normal hematopoietic stem cells could improve outcomes while avoiding much of the toxicities associated with conventional chemotherapy and other targeted therapeutics.”
Mandalam says they are now doing the late-stage preclinical testing to be able to apply to the Food and Drug Administration for permission to start a clinical trial. CIRM is funding this stage of the research.