Glioblastoma is an aggressive form of cancer that invades brain tissue, making it extremely difficult to treat. Current therapies involving radiation and chemotherapy are effective in destroying the bulk of brain cancer cells, but they are not able to reach the brain cancer stem cells, which have the ability to grow and multiply indefinitely. These cancer stem cells enable the glioblastoma to continuously grow even after treatment, which leads to recurring tumor formation.
Dr. Jeremy Rich and his team at UC San Diego examined glioblastomas further by obtaining glioblastoma tumor samples donated by patients that underwent surgery and implanting these into mice. Dr. Rich and his team tested a combinational treatment that included a targeted cancer therapy alongside a drug named teriflunomide, which is used to treatment patients with multiple sclerosis. The research team found that this approach successfully halted the growth of glioblastoma stem cells, shrank the tumor size, and improved survival in the mice.
In order to continue replicating, glioblastoma stem cells make pyrimidine, one of the compounds that make up DNA. Dr. Rich and his team noticed that higher rates of pyrimidine were associated with poor survival rates in glioblastoma patients. Teriflunomide works by blocking an enzyme that is necessary to make pyrmidine, therefore inhibiting glioblastoma stem cell replication.
In a press release, Dr. Rich talks about the potential these findings hold by stating that,
“We’re excited about these results, especially because we’re talking about a drug that’s already known to be safe in humans.”
However, he comments on the need to evaluate this approach further by saying that,
“This laboratory model isn’t perfect — yes it uses human patient samples, yet it still lacks the context a glioblastoma would have in the human body, such as interaction with the immune system, which we know plays an important role in determining tumor growth and survival. Before this drug could become available to patients with glioblastoma, human clinical trials would be necessary to support its safety and efficacy.”
The full results to this study were published in Science Translational Medicine.
In ancient Greek mythology, a Chimera was a creature that was usually depicted as a lion with an additional goat head and a serpent for a tail. Due to the Chimera’s animal hybrid nature, the term “chimeric” came to fruition in the scientific community as a way to describe an organism containing two or more different sets of DNA.
A CIRM-funded study conducted by Dr. Mathew Blurton-Jones and his team at UC Irvine describes a way for human brain immune cells, known as microglia, to grow and function inside mice. Since the mice contain a both human cells and their own mice cells, they are described as being chimeric.
In order to develop this chimeric “mighty mouse” model, Dr. Blurton-Jones and his team generated induced pluripotent stem cells (iPSCs), which have the ability to turn into any kind of cell, from cell samples donated by adult patients. For this study, the researchers converted iPSCs into microglia, a type of immune cell found in the brain, and implanted them into genetically modified mice. After a few months, they found that the implanted cells successfully integrated inside the brains of the mice.
By finding a way to look at human microglia grow and function in real time in an animal model, scientists can further analyze crucial mechanisms contributing to neurological conditions such as Alzheimer’s, Parkinson’s, traumatic brain injury, and stroke.
For this particular study, Dr. Blurton-Jones and his team looked at human microglia in the mouse brain in relation to Alzheimer’s, which could hold clues to better understand and treat the disease. The team did this by introducing amyloid plaques, protein fragments in the brain that accumulate in people with Alzheimer’s, and evaluating how the human microglia responded. They found that the human microglia migrated toward the amyloid plaques and surrounding them, which is what is observed in Alzheimer’s patients.
In a press release, Dr. Blurton-Jones expressed the importance of studying microglia by stating that,
“Microglia are now seen as having a crucial role in the development and progression of Alzheimer’s. The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer’s and the majority of these are switched on in microglia. However, so far we’ve only been able to study human microglia at the end stage of Alzheimer’s in post-mortem tissues or in petri dishes.”
Furthermore, Dr. Blurton-Jones highlighted the importance of looking at human microglia in particular by saying that,
“The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cell.”
The full results of this study were published in Cell.
Getting a breast cancer diagnosis is devastating news in and of itself. Currently, there are treatment options that target three different types of receptors, which are named hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR), commonly found in breast cancer cells, . Unfortunately, in triple-negative breast cancer, which occurs in 10-20% of breast cancer cases, all three receptors are absent, making this form of breast cancer very aggressive and difficult to treat.
In recent years, researchers have discovered that proteins on the cell surface can tell macrophages, an immune cell designed to detect and engulf foreign or abnormal cells, not to eat and destroy them. This can be useful to help normal cells keep the immune system from attacking them, but cancer cells can also use these “don’t eat me” signals to hide from the immune system.
In fact, because of this concept, a CIRM-funded clinical trial is being conducted that uses an antibody called 5F9 to block a “don’t eat me” signal known as CD47 that is found in cancer cells. The results of this trial, which have been announced in a previous blog post, are very promising.
Further building on this concept, a CIRM-funded study has now discovered a potential new target for triple-negative breast cancer as well as ovarian cancer. Dr. Irv Weissman and a team of researchers at Stanford University have discovered an additional “don’t eat me” signal called CD24 that cancers seem to use to evade detection and destruction by the immune system.
In a press release, Dr. Weissman talks about his work with CD47 and states that,
“Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative ‘don’t eat me’ signals.”
The scientists began by looking for signals that were produced more highly in cancers than in the tissues from which the cancers arose. It is here that they discovered CD24 and then proceeded to implant human breast cancer cells in mice for testing. When the CD24 signaling was blocked, the mice’s immune system attacked the cancer cells.
An important discovery was that ovarian and triple-negative breast cancer were highly affected by blocking of CD24 signaling. The other interesting discovery was that the effectiveness of CD24 blockage seems to be complementary to CD47 blockage. In other words, some cancers, like blood cancers, seem to be highly susceptible to blocking CD47, but not to CD24 blockage. For other cancers, like ovarian cancer, the opposite is true. This could suggest that most cancers will be susceptible to the immune system by blocking the CD24 or CD47 signal, and that cancers may be even more vulnerable when more than one “don’t eat me” signal is blocked.
Dr. Weissman and his team are now hopeful that potential therapies to block CD24 signaling will follow in the footsteps of the clinical trials related to CD47.
In addition to approving funding for breast cancer related brain metastases last week, the CIRM Board also approved an additional $19.7 million geared towards our 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.
Before getting into the details of each project, here is a table with a brief synopsis of the awards:
TRAN1 – 11532
$3.73 million was awarded to Dr. Mark Humayun at USC to develop a novel therapeutic product capable of slowing the progression of age-related macular degeneration (AMD).
AMD is an eye disease that causes severe vision impairment, resulting in the inability to read, drive, recognize faces, and blindness if left untreated. It is the leading cause of vision loss in the U.S. and currently affects over 2 million Americans. By the year 2050, it is projected that the number of affected individuals will more than double to over 5 million. A layer of cells in the back of the eye called the retinal pigment epithelium (RPE) provide support to photoreceptors (PRs), specialized cells that play an important role in our ability to process images. The dysfunction and/or loss of RPE cells plays a critical role in the loss of PRs and hence the vision problems observed in AMD. One form of AMD is known as dry AMD (dAMD) and accounts for about 90% of all AMD cases.
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 dAMD, supporting the survival of photoreceptors in the affected retina.
TRAN1 – 11579
$6.23 million was awarded to Dr. Mark Tuszynski at UCSD to develop a neural stem cell therapy for spinal cord injury (SCI).
According to data from the National Spinal
Cord Injury Statistical Center, as of 2018, SCI affects an estimated 288,000
people in the United States alone, with about 17,700 new cases each year. There
are currently no effective therapies for SCI. Many people suffer SCI in early
adulthood, leading to life-long disability and suffering, extensive treatment
needs and extremely high lifetime costs of health care.
The approach that Dr. Tuszynski is developing will use hESCs to create neural stem cells (NSCs). These newly created NSCs would then be grafted at the site of injury of those with SCI. In preclinical studies, the NSCs have been shown to support the formation of neuronal relays at the site of SCI. The neuronal relays allow the sensory neurons in the brain to communicate with the motor neurons in the spinal cord to re-establish muscle control and movement.
TRAN1 – 11548
$4.83 million was awarded to Dr. Brian Cummings at UC Irvine to develop a neural stem cell therapy for traumatic brain injury (TBI).
TBI is caused by a bump, blow, or jolt to the head that disrupts the normal function of the brain, resulting in emotional, mental, movement, and memory problems. There are 1.7 million people in the United States experiencing a TBI that leads to hospitalization each year. Since there are no effective treatments, TBI is one of the most critical unmet medical needs based on the total number of those affected and on a cost basis.
The approach that Dr. Cummings is developing will also use hESCs to create NSCs. These newly created NSCs would be integrated with injured tissue in patients and have the ability to turn into the three main cell types in the brain; neurons, astrocytes, and oligodendrocytes. This would allow for TBI patients to potentially see improvements in issues related to memory, movement, and anxiety, increasing independence and lessening patient care needs.
TRAN1 – 11628
$4.96 million was awarded to Dr. Evan Snyder at Sanford Burnham Prebys to develop a neural stem cell therapy for perinatal hypoxic-ischemic brain injury (HII).
HII occurs when there is a lack of oxygen flow to the brain. A newborn infant’s body can compensate for brief periods of depleted oxygen, but if this lasts too long, brain tissue is destroyed, which can cause many issues such as developmental delay and motor impairment. Current treatment for this condition is whole-body hypothermia (HT), which consists of significantly reducing body temperature to interrupt brain injury. However, this is not very effective in severe cases of HII.
The approach that Dr. Snyder is developing will use an established neural stem cell (NSC) line. These NSCs would be injected and potentially used alongside HT treatment to increase protection from brain injury.
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.
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.”
In the United States alone, there are approximately 1.1 million people living with Human immunodeficiency virus (HIV), a virus that weakens the immune system by destroying important cells that fight off disease and infection. This number is much larger on a global scale, with 36.9 million people living with HIV as of 2017. If left untreated, the immune system becomes so weakened that the condition worsens into acquired immunodeficiency syndrome (AIDS), which is usually fatal.
Current treatment for HIV focuses on the use of antiretroviral therapy (ART). This treatment is able to suppress replication of the virus, but it does not eliminate it from the body entirely. In order to be sustainable, ART must be taken throughout the course of a lifetime, otherwise HIV rebounds and the replication of the virus renews, fueling the development of AIDS.
The ability of HIV to rebound is related to the fact that it is able to integrate its DNA into various cells inside the body and beyond the reach of ART. Here they are able to remain dormant and ready to replicate as soon as ART is not interfering. It is because of this that ART is not sufficient on its own to cure HIV, but a group of scientists have uncovered a promising breakthrough to change that.
In a major collaboration, researchers at the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center (UNMC) have for the first time eliminated HIV from the DNA of living mice. This study marks a critical step toward the development of a possible cure for human HIV infection.
The team of researchers was able to do this with the help of a new technology called long-acting slow-effective release (LASER) ART. LASER ART is able to target HIV sanctuaries and maintain replication at low levels for extended periods of time. Immediately after administering LASER ART, the team used a gene editing technology known as CRISPR to remove the final remnants of HIV DNA hidden inside cells.
In a press release, Dr. Kamel Khalili, senior investigator for this study, was quoted as saying,
“Our study shows that treatment to suppress HIV replication and gene editing therapy, when given sequentially, can eliminate HIV from cells and organs of infected animals…We now have a clear path to move ahead to trials in non-human primates and possibly clinical trials in human patients within the year.”
The full results of this study were published in Nature Communications.
To learn more about how CRISPR technology works, you can read more about it on a previous blog post.
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.
While we are here at ISSCR 2019 hearing various scientists talk about their work, we realize that there are various breakthroughs in stem cell research in a wide variety of different fields going on every day. It is wonderful to see how scientists are hard at work in developing the latest science and pushing innovation. Here are two remarkable stories you may have missed this week.
Scientists developing way to help premature babies breathe easier
Researchers at Cincinnati Children’s Hospital Medical Center are looking at ways to stimulate lung development in premature infants who suffer from a rare condition called Bronchopulmonary Dysplasia (BPD), which can cause lifelong breathing problems and even death. Using a mouse model of BPD, extensive analysis, and testing, the scientists were able to create a proposal to develop a stem cell therapy based on what are called c-KIT endothelial progenitor cells.
Premature babies, unable to breathe on their own, rely on machines to help them breathe. Unfortunately, these machines can interfere with lung development as well. The cells proposed in the stem cell therapy are common in the lungs of infants still in the womb and help in the formation of capillaries and air sacs in the lungs called alveoli.
In a press release, Dr. Vlad Kalinichenko, lead investigator for this work, was quoted as saying,
“The cells are highly sensitive to injury by high oxygen concentrations, so lung development in premature babies on mechanical oxygen assistance is impeded. Our findings suggest using c-KIT-positive endothelial cells from donors, or generating them with pluripotent stem cells, might be a way to treat BPD or other pediatric lung disorders associated with loss of alveoli and pulmonary microvasculature.”
The full results were published in American Journal of Respiratory and Critical Care Medicine.
Mice with a human immune system help research into cancer and infections
Speaking of a mouse model, researchers from Aarhus University and Aarhus University Hospital have succeeded in using mice with a transplanted human immune system to study functions in the immune system which are otherwise particularly difficult to study. This work could open the possibilities towards looking further into disease areas such as cancer, HIV, and autoimmune diseases.
Before potential treatments can be tested in humans, there needs to be extensive animal testing and data generated. However, when the disease relate’s to the human immune system, it can be particularly challenging to evaluate this in mice. The research team succeeded in transplanting human stem cells into mice whose own immune system is disabled, and then triggered a type of reaction in the immune system which normally reacts to meeting a range of viruses and bacteria.
In a press release, Dr. Anna Halling Folkmar, one of the researchers behind the study, says that,
“The humanised mice are an important tool in understanding how human immune cells behave during diseases and how they react to different medical treatments.”