Heart disease continues to be the number one cause of death in the United States. An estimated 375,000 people have a genetic form of heart disease known as familial dilated cardiomyopathy. This occurs when the heart muscle becomes weakened in one chamber in the heart, causing the open area of the chamber to become enlarged or dilated. As a result of this, the heart can no longer beat regularly, causing shortness of breath, chest pain and, in severe cases, sudden and deadly cardiac arrest.
A CIRM funded study by a team of researchers at Stanford University looked further into this form of genetic heart disease by taking a patient’s skin cells and converting them into stem cells known as induced pluripotent stem cells (iPSCs), which can become any type of cell in the body. These iPSCs were then converted into heart muscle cells that pulse just as they do in the body. These newly made heart muscle cells beat irregularly, similar to what is observed in the genetic heart condition.
Upon further analysis, the researchers linked a receptor called PGDF to cause various genes to be more highly activated in the mutated heart cells compared to normal ones. Two drugs, crenolanib and sunitinib, interfere with the PGDF receptor. After treating the abnormal heart cells, they began beating more regularly, and their gene-activation patterns more closely matched those of cells from healthy donors.
These two drugs are already FDA-approved for treating various cancers, but previous work shows that the drugs may damage the heart at high doses. The next step would be determining the right dose of the drug. The current study is part of a broader effort by the researchers to use these patient-derived cells-in-a-dish to screen for and discover new drugs.
Dr. Joseph Wu, co-senior author of this study, and his team have generated heart muscle cells from over 1,000 patients, including those of Dr. Wu, his son, and his daughter. In addition to using skin cells, the same technique to create heart cells from patients can also be done with 10 milliliters of blood — roughly two teaspoons.
“With 10 milliliters of blood, we can make clinically usable amounts of your beating heart cells in a dish…Our postdocs have taken my blood and differentiated my pluripotent stem cells into my brain cells, heart cells and liver cells. I’m asking them to test some of the medications that I might need to take in the future.”
A sense of balance is important for a wide range of activities, from simple ones such as walking, running, and driving, to more intricate ones such as dancing, rock climbing, and tight-rope walking. A lack of physical balance in the body can lead to an inbalance in trying to live a normal everyday life.
One primary cause of balance disorders is a problem with hair cells located inside the inner ear, which play a role in maintaining balance, spatial orientation, and regulating eye movement. Damage to these cells can occur as a result from infections, genetic disorders, or aging. Unfortunately, in humans, hair cells in the inner ear regenerate on their own very minimally. In the United States alone, 69 million people experience balance disorders. Symptoms of this disorder include a “spinning” feeling, lack of balance, nausea, and difficulty tracking objects using the eyes.
However, a CIRM funded study has showed promising results for helping treat this disorder. Researchers at Stanford University have discovered a way to regenerate hair cells in the inner ear of mice, giving them a better sense of balance. To do this, the researchers impaired the hair cells in the inner ear of mice and measured how well they regenerated on their own to obtain a baseline measurement. They found that about a third of the cells regenerated on their own.
Next, the researchers manipulated Atoh1, a transcription factor that regulates hair cell formation in mice. By overexpressing Atoh1, the researchers found that as much as 70% of hair cells regenerated in the mice. Additionally, 70% of these mice also recovered their sense of balance. This simple proof of concept could potentially be applied in humans to treat similar disorders related to the loss of hair cells in the inner ear.
In a press release, Dr. Alan Cheng, senior author of this study, is quoted as saying,
“This is very exciting. It’s an important first step to find treatment for vestibular disorders. We couldn’t get sufficient regeneration to recover function before.”
Here at CIRM, we get calls every day from patients asking us if there are any trials or therapies available to treat their illness or an illness affecting a loved one. Unfortunately, there are some predatory clinics that try to take advantage of this desperation by advertising unproven and unregulated treatments for a wide range of diseases such as Diabetes, Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS).
A recent article in the Los Angeles Times describes how one of these predatory stem cell clinics is in a class action lawsuit related to false advertising of 100% patient satisfaction. Patients were led to believe that this percentage was related to the effectiveness of the treatment, when in fact it had to do with satisfaction related to hospitality, hotel stay, and customer service. These kinds of deceptive tactics are commonplace for sham clinics and are used to convince people to pay tens of thousands of dollars for sham treatments.
how can a patient or loved one distinguish a legitimate clinical trial or
treatment from those being offered by predatory clinics? We have established
the “fundamental three R’s” to help in making this distinction.
United States Food and Drug Administration (FDA) has a regulated process
that it uses in evaluating potential treatments from researchers seeking
approval to test these in a clinical trial setting. This includes extensive reviews by scientific
peers in the community that are well informed on specific disease areas. Those
that adhere to these regulations get an FDA seal of approval and are subject to
extensive oversight to protect patients participating in this trial.
Additionally, these regulations ensure that the potential treatments are
properly evaluated for effectiveness. The 55 clinical trials
that we have currently funded as well as the clinical trials being conducted in our Alpha Stem Cell Clinic
Network all have this FDA seal of approval. In contrast to this,
the treatments offered at predatory clinics have not gone through the rigorous
standards necessary to obtain FDA approval.
We have partnered with reputable institutions to carry out the clinical trials we have funded and establish our Alpha Stem Cell Clinic Network. These are institutions that adhere to the highest scientific standards necessary to effectively evaluate potential treatments and communicate these results with extreme accuracy. These institutions have expert scientists, doctors, and nurses in the field and adhere to rigorous standards that have earned these institutions a positive reputation for carrying out their work. The sites for the Alpha Stem Cell Clinic Network include City of Hope, UCSF, UC San Diego, UCLA, UC Davis, and UC Irvine. In regards to the clinical trials we have directly funded, we have collaborated with other prestigious institutions such as Stanford and USC. All these institutions have a reputation for being respected by established societies and other professionals in the field. The reputation that predatory clinics have garnered from patients, scientists, and established doctors has been a negative one. An article published in The New York Times has described the tactics used by these predatory clinics as unethical and their therapies have often been shown to be ineffective.
The clinical trials we fund and those offered at our Alpha Stem Cell Clinic Network are reliable because they are trusted by patients, patient advocacy groups, and other experts in the field of regenerative medicine. A part of being reliable involves having extensive expertise and training to properly evaluate and administer treatments in a clinical trial setting. The doctors, nurses, and other experts involved in clinical trials given the go-ahead by the FDA have extensive training to carry out these trials. These credentialed specialists are able to administer high quality clinical care to patients. In a sharp contrast to this, an article published in Reuters showed that predatory clinics not only administer unapproved stem cell treatments to patients, but they use doctors that have not received training related to the services they provide.
you are looking at a potential clinical trial or treatment for yourself or a
loved one, just remember the 3 R’s we have laid out in this blog.
A transplant can be a lifesaving procedure for many people across the United States. In fact, according to the Health Resources & Services Administration, 36,528 transplants were performed in 2018. However, as of January 2019, the number of men, women, and children on the national transplant waiting list is over 113,000, with 20 people dying each day waiting for a transplant and a new person being added to the list every 10 minutes.
Before considering a transplant, there needs to be an immunological match between the donated tissue and/or blood stem cells and the recipient. To put it simply, a “match” indicates that the donor’s cells will not be marked by the recipient’s immune cells as foreign and begin to attack it, a process known as graft-versus-host disease. Unfortunately, these matches can be challenging to find, particularly for some ethnic minorities. Often times, immunosuppression drugs are also needed in order to prevent the foreign cells from being attacked by the body’s immune system. Additionally, chemotherapy and radiation are often needed as well.
Fortunately, a CIRM-funded study at Stanford has shown some promising results towards addressing the issue of matching donor cells and recipient. Dr. Irv Weissman and his colleagues at Stanford have found a way to prepare mice for a transplant of blood stem cells, even when donor and recipient are an immunological mismatch. Their method involved using a combination of six specific antibodies and does not require ongoing immunosuppression.
The combination of antibodies did this by eliminating several types of immune cells in the animals’ bone marrow, which allowed blood stem cells to engraft and begin producing blood and immune cells without the need for continued immunosuppression. The blood stem cells used were haploidentical, which, to put it simply, is what naturally occurs between parent and child, or between about half of all siblings.
Additional experiments also showed that the mice treated with the six antibodies could also accept completely mismatched purified blood stem cells, such as those that might be obtained from an embryonic stem cell line.
The results established in this mouse model could one day lay the foundation necessary to utilize this approach in humans after conducting clinical trials. The idea would be that a patient that needs a transplanted organ could first undergo a safe, gentle transplant with blood stem cells derived in the laboratory from embryonic stem cells. The same embryonic stem cells could also then be used to generate an organ that would be fully accepted by the recipient without requiring the need for long-term treatment with drugs to suppress the immune system.
“With support by the California Institute for Regenerative Medicine, we’ve been able to make important advances in human embryonic stem cell research. In the past, these stem cell transplants have required a complete match to avoid rejection and reduce the chance of graft-versus-host disease. But in a family with four siblings the odds of having a sibling who matches the patient this closely are only one in four. Now we’ve shown in mice that a ‘half match,’ which occurs between parents and children or in two of every four siblings, works without the need for radiation, chemotherapy or ongoing immunosuppression. This may open up the possibility of transplant for nearly everyone who needs it. Additionally, the immune tolerance we’re able to induce should in the future allow the co-transplantation of [blood] stem cells and tissues, such as insulin-producing cells or even organs generated from the same embryonic stem cell line.”
The full results to this study were published in Cell Stem Cell.
From Day One CIRM’s goal has been to advance stem cell research in California. We don’t do that just by funding the most promising research -though the 51 clinical trials we have funded to date clearly shows we do that rather well – but also by trying to bring the best minds in the field together to overcome problems.
Over the years we
have held conferences, workshops and symposiums on everything from Parkinson’s
palsy and tissue
engineering. Each one attracted the key players and stakeholders in the
field, brainstorming ideas to get past obstacles and to explore new ways of
developing therapies. It’s an attempt to get scientists, who would normally be
rivals or competitors, to collaborate and partner together in finding the best
It’s not easy to do,
and the results are not always obvious right away, but it is essential if we
hope to live up to our mission of accelerating stem cell therapies to patients
with unmet medical needs.
For example. This
past week we helped organize two big events and were participants in another.
The first event we
pulled together, in partnership with Cedars-Sinai Medical Center, was a
workshop called “Brainstorm Neurodegeneration”. It brought together leaders in stem
cell research, genomics, big data, patient advocacy and the Food and Drug
Administration (FDA) to tackle some of the issues that have hampered progress
in finding treatments for things like Parkinson’s, Alzheimer’s, ALS and
ambitiously subtitled the workshop “a cutting-edge meeting to disrupt the field”
and while the two days of discussions didn’t resolve all the problems facing us
it did produce some fascinating ideas and some tantalizing glimpses at ways to
advance the field.
Two days later we partnered with UC San Francisco to host the Fourth Annual CIRM Alpha Stem Cell Clinics Network Symposium. This brought together the scientists who develop therapies, the doctors and nurses who deliver them, and the patients who are in need of them. The theme was “The Past, Present & Future of Regenerative Medicine” and included both a look at the initial discoveries in gene therapy that led us to where we are now as well as a look to the future when cellular therapies, we believe, will become a routine option for patients.
different groups together is important for us. We feel each has a key role to
play in moving these projects and out of the lab and into clinical trials and
that it is only by working together that they can succeed in producing the
treatments and cures patients so desperately need.
As always it was the patients who surprised us. One, Cierra Danielle Jackson, talked about what it was like to be cured of her sickle cell disease. I think it’s fair to say that most in the audience expected Cierra to talk about her delight at no longer having the crippling and life-threatening condition. And she did. But she also talked about how hard it was adjusting to this new reality.
Cierra said sickle
cell disease had been a part of her life for all her life, it shaped her daily
life and her relationships with her family and many others. So, to suddenly
have that no longer be a part of her caused a kind of identity crisis. Who was
she now that she was no longer someone with sickle cell disease?
She talked about how
people with most diseases were normal before they got sick, and will be normal
after they are cured. But for people with sickle cell, being sick is all they
have known. That was their normal. And now they have to adjust to a new normal.
It was a powerful
reminder to everyone that in developing new treatments we have to consider the
whole person, their psychological and emotional sides as well as the physical.
And so on to the third event we were part of, the Stanford Drug Discovery Symposium. This was a high level, invitation-only scientific meeting that included some heavy hitters – such as Nobel Prize winners Paul Berg and Randy Schekman, former FDA Commissioner Robert Califf. Over the course of two days they examined the role that philanthropy plays in advancing research, the increasingly important role of immunotherapy in battling diseases like cancer and how tools such as artificial intelligence and big data are shaping the future.
CIRM’s President and CEO, Dr. Maria Millan, was one of those invited to speak and she talked about how California’s investment in stem cell research is delivering Something Better than Hope – which by a happy coincidence is the title of our 2018 Annual Report. She highlighted some of the 51 clinical trials we have funded, and the lives that have been changed and saved by this research.
The presentations at
these conferences and workshops are important, but so too are the conversations
that happen outside the auditorium, over lunch or at coffee. Many great
collaborations have happened when scientists get a chance to share ideas, or
when researchers talk to patients about their ideas for a successful clinical
It’s amazing what happens when you bring people together who might otherwise never have met. The ideas they come up with can change the world.
At CIRM we are very cautious about using the “c” word. Saying someone has been “cured” is a powerful statement but one that loses its meaning when over used or used inappropriately. However, in the case of a new study from U.C. San Francisco and St. Jude Children’s Research Hospital in Memphis, saying “cure” is not just accurate, it’s a celebration of something that would have seemed impossible just a few years ago.
The research focuses on children with a specific form of Severe Combined Immunodeficiency (SCID) called X-Linked SCID. It’s also known as “bubble baby” disease because children born with this condition lack a functioning immune system, so even a simple infection could be fatal and in the past they were kept inside sterile plastic bubbles to protect them.
In this study, published in the New England Journal of Medicine, researchers took blood stem
cells from the child and, in the lab, genetically re-engineered them to correct
the defective gene, and then infused them back into the child. Over time they
multiplied and created a new blood supply, one free of the defect, which helped
repair the immune system.
In a news
release Dr. Ewelina Mamcarz, the lead author of the study, announced that
ten children have been treated with this method.
“These patients are toddlers now, who are responding to
vaccinations and have immune systems to make all immune cells they need for
protection from infections as they explore the world and live normal lives.
This is a first for patients with SCID-X1.”
The ten children were treated at both St. Jude and at UCSF
funded the UCSF arm of the clinical trial.
The story, not surprisingly, got a lot of attention in the
media including this fine
piece by CNN.
A variety of diseases can be traced to a simple root cause: problems in the bone marrow. The bone marrow contains specialized stem cells known as hematopoietic stem cells (HSCs) that give rise to different types of blood cells. As mentioned in a previous blog about Sickle Cell Disease (SCD), one problem that can occur is the production of “sickle like” red blood cells. In blood cancers like leukemia, there is an uncontrollable production of abnormal white blood cells. Another condition, known as myelodysplastic syndromes (MDS), are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells.
For diseases that originate in the bone marrow, one treatment involves introducing healthy HSCs from a donor or gene therapy. However, before this type of treatment can take place, all of the problematic HSCs must be eliminated from the patient’s body. This process, known as pre-treatment, involves a combination of chemotherapy and radiation, which can be extremely toxic and life threatening. There are some patients whose condition has progressed to the point where their bodies are not strong enough to withstand pre-treatment. Additionally, there are long-term side effects that chemotherapy and radiation can have on infant children that are discussed in a previous blog about pediatric brain cancer.
Could there be a targeted, non-toxic approach to eliminating unwanted HSCs that can be used in combination with stem cell therapies? Researchers at Stanford say yes and have very promising results to back up their claim.
Dr. Judith Shizuru and her team at Stanford University have developed an antibody that can eliminate problematic blood forming stem cells safely and efficiently. The antibody is able to identify a protein on HSCs and bind to it. Once it is bound, the protein is unable to function, effectively removing the problematic blood forming stem cells.
Dr. Shizuru is the senior author of a study published online on February 11th, 2019 in Blood that was conducted in mice and focused on MDS. The results were very promising, demonstrating that the antibody successfully depleted human MDS cells and aided transplantation of normal human HSCs in the MDS mouse model.
This proof of concept holds promise for MDS as well as other disease conditions. In a public release from Stanford Medicine, Dr. Shizuru is quoted as saying, “A treatment that specifically targets only blood-forming stem cells would allow us to potentially cure people with diseases as varied as sickle cell disease, thalassemia, autoimmune disorders and other blood disorders…We are very hopeful that this body of research is going to have a positive impact on patients by allowing better depletion of diseased cells and engraftment of healthy cells.”
The research mentioned was partially funded by us at CIRM. Additionally, we recently awarded a $3.7 million dollar grant to use the same antibody in a human clinical trial for the so-called “bubble baby disease”, which is also known as severe combined immunodeficiency (SCID). You can read more about that award on a previous blog post linked here.
Imagine being told that your seemingly healthy newborn baby has a life-threatening disease. In a moment your whole world is turned upside down. That’s the reality for families with a child diagnosed with severe combined immunodeficiency (SCID). Children with SCID lack a functioning immune system so even a simple cold can prove fatal. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $3.7 million to develop a new approach that could help these children.
The funding will enable Stanford’s Dr. Judith Shizuru to complete
an earlier CIRM-funded Phase 1 clinical trial using a chemotherapy-free
transplant procedure for SCID.
The goal of the project is to replace SCID patients’ dysfunctional immune cells with healthy ones using a safer form of bone marrow transplant (BMT). Current BMT procedures use toxic chemotherapy to make space in the bone marrow for the healthy transplanted stem cells to take root and multiply. The Stanford team is testing a safe, non-toxic monoclonal antibody that targets and removes the defective blood forming stem cellsin order to promote the engraftment of the transplanted stem cells in the patient.
The funding is contingent on Dr. Shizuru raising $1.7
million in co-funding by May 1 of this year.
“This research highlights two of the things CIRM was
created to do,” says Maria T. Millan, MD, President & CEO of CIRM. “We fund
projects affecting small numbers of patients, something many organizations or
companies aren’t willing to do, and we follow those projects from the bench to
the bedside, supporting them every step along the way.”
Early testing has shown promise in helping patients and
it’s hoped that if this approach is successful in children with SCID it may
also open up similar BMT therapies for patients with other auto-immune diseases
such as multiple sclerosis, lupus or diabetes.
Neurological diseases are among the most daunting diagnoses for a patient to receive, because they impact how the individual interacts with their surroundings. Central to our ability to provide better treatment options for these patients, is scientists’ capability to understand the biological factors that influence disease development and progression. Researchers at the Stanford University School of Medicine have made an important step in providing neuroscientists a better tool to understand the brain.
While animal models are excellent systems to study the intricacies of different diseases, the ability to translate any findings to humans is relatively limited. The next best option is to study human stem cell derived tissues in the laboratory. The problem with the currently available laboratory-derived systems for studying the brain, however, is the limited longevity and diversity of neuronal cell types. Dr. Sergiu Pasca’s team was able to overcome these hurdles, as detailed in their study, published in the journal Nature Neuroscience.
A new approach
Specifically, Dr. Pasca’s group developed a method to differentiate or transform skin derived human induced pluripotent stem cells (iPSCs – which are capable of becoming any cell type) into brain-like structures that mimic how oligodendrocytes mature during brain development. Oligodendrocytes are most well known for their role in myelinating neurons, in effect creating a protective sheath around the cell to protect its ability to communicate with other brain cells. Studying oligodendrocytes in culture systems is challenging because they arise later in brain development, and it is difficult to generate and maintain them with other cell types found in the brain.
These scientists circumvented this problem by using a unique combination of growth factors and nutrients to culture the oligodendrocytes, and found that they behaved very similarly to oligodendrocytes isolated from humans. Most excitingly, they observed that the stem cell-derived oligodendrocytes were able to myelinate other neurons in the culture system. Therefore they were both physically and functionally similar to human oligodendrocytes.
Importantly, the scientists were also able to generate astrocytes alongside the oligodendrocytes. Astrocytes perform many important functions such as providing essential nutrients and directing the electrical signals that help cells in the brain communicate with each other. In a press release, Dr. Pasca explains the importance of generating multiple cell types in this in vitro system:
“We now have multiple cell types interacting in one single
culture. This permits us to look close-up at how the main cellular players in
the human brain are talking to each other.”
This in vitro or laboratory-developed system has the potential to help scientists better understand oligodendrocytes in the context of diseases such as multiple sclerosis and cerebral palsy, both of which stem from improper myelination of brain nerve cells.
This work was partially supported by a CIRM grant.
If you were looking for a poster child for an unmet medical need Huntington’s disease (HD) would be high on the list. It’s a devastating disease that attacks the brain, steadily destroying the ability to control body movement and speech. It impairs thinking and often leads to dementia. It’s always fatal and there are no treatments that can stop or reverse the course of the disease. Today the Board of the California Institute for Regenerative Medicine (CIRM) voted to support a project that shows promise in changing that.
The Board voted to approve $6 million to enable Dr. Leslie Thompson and her team at the University of California, Irvine to do the late stage testing needed to apply to the US Food and Drug Administration for permission to start a clinical trial in people. The therapy involves transplanting stem cells that have been turned into neural stem cells which secrete a molecule called brain-derived neurotrophic factor (BDNF), which has been shown to promote the growth and improve the function of brain cells. The goal is to slow down the progression of this debilitating disease.
“Huntington’s disease affects around 30,000 people in the US and children born to parents with HD have a 50/50 chance of getting the disease themselves,” says Dr. Maria T. Millan, the President and CEO of CIRM. “We have supported Dr. Thompson’s work for a number of years, reflecting our commitment to helping the best science advance, and are hopeful today’s vote will take it a crucial step closer to a clinical trial.”
Another project supported by CIRM at an earlier stage of research was also given funding for a clinical trial.
The Board approved almost $12 million to support a clinical trial to help people undergoing a kidney transplant. Right now, there are around 100,000 people in the US waiting to get a kidney transplant. Even those fortunate enough to get one face a lifetime on immunosuppressive drugs to stop the body rejecting the new organ, drugs that increase the risk for infection, heart disease and diabetes.
Dr. Everett Meyer, and his team at Stanford University, will use a combination of healthy donor stem cells and the patient’s own regulatory T cells (Tregs), to train the patient’s immune system to accept the transplanted kidney and eliminate the need for immunosuppressive drugs.
The initial group targeted in this clinical trial are people with what are called HLA-mismatched kidneys. This is where the donor and recipient do not share the same human leukocyte antigens (HLAs), proteins located on the surface of immune cells and other cells in the body. Around 50 percent of patients with HLA-mismatched transplants experience rejection of the organ.
In his application Dr. Meyer said they have a simple goal: “The goal is “one kidney for life” off drugs with safety for all patients. The overall health status of patients off immunosuppressive drugs will improve due to reduction in side effects associated with these drugs, and due to reduced graft loss afforded by tolerance induction that will prevent chronic rejection.”