The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.
In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”
The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.
“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”
Speaking of cancer….
Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.
In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.
In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”
So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.
They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.
Multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020. Unfortunately, many patients with this type of blood cancer eventually develop resistance to multiple types of treatments. This phenomenon is partially due to the fact that cancer stem cells, which have the ability to evade traditional therapies and then self-renew, help drive the disease.
It is for this reason that a team of researchers, at the UC San Diego School of Medicine and Ionis Pharmaceuticals, are developing a therapy that can destroy these malignant stem cells, thereby preventing the cancer from coming back. With support from CIRM, the team developed an approach that interacts with IRF4, a gene that allows myeloma stem cells and tumor cells to grow and survive chemotherapy and radiation. They have engineered an oligonucleotide, a short DNA molecule, to prevent IRF4 from functioning. The therapy, known as ION251, lowered disease burden, reduced the amount of myeloma stem cells, and increased survival when tested in mice bearing human myeloma. These results have enabled the team to start a Phase I clinical trial to see if this approach is safe and effective in people with myeloma.
To study the disease and test ION251, the team transplanted human myeloma cells into mice that lack an immune system and thus won’t reject human cells. Ten mice received the ION251 treatment and an additional ten mice received a control treatment. After receiving the ION251 therapy, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. Additionally, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did.
In a news release from UC San Diego Health, Dr. Leslie Crews, co-senior author and assistant professor at the UCSD School of Medicine, elaborated on the promising results from the mouse study.
“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank — in the treated mice, we couldn’t find any myeloma cells left for us to study. It makes the science more difficult, but it gives me hope for patients.”
The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information on this can be viewed by clicking the link here.
The full results of this study were published in the journal Cell Stem Cell.
Rett syndrome is a rare form of autism spectrum disorder that impairs brain development and causes problems with movement, speech, and even breathing. It is caused by mutations in a gene called MECP2 and primarily affects females. Although there are therapies to alleviate symptoms, there is currently no cure for this genetic disorder.
With CIRM funding ($1.37M and $1.65M awards), Alysson Muotri, PhD and a team of researchers at the University of California San Diego School of Medicine and Sanford Consortium for Regenerative Medicine have used brain organoids that mimic Rett syndrome to identify two drug candidates that returned the “mini-brains” to near-normal. The drugs restored calcium levels, neurotransmitter production, and electrical impulse activity.
Brain organoids, also referred to as “mini-brains”, are 3D models made of cells that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study changes in physical structure or gene expression over time.
Dr. Muotri and his team created induced pluripotent stem cells (iPSCs), a type of stem cell that can become virtually any type of cell. For the purposes of this study, they were created from the skin cells of Rett syndrome patients. The newly created iPSCs were then turned into brain cells and used to create “mini-brains”, thereby preserving each Rett syndrome patient’s genetic background. In addition to this, the team also created “mini-brains” that artificially lack the MECP2 gene, mimicking the issues with the same gene observed in Rett syndrome.
Lack of the MECP2 gene changed many things about the “mini-brains” such as shape, neuron subtypes present, gene expression patterns, neurotransmitter production, and decreases in calcium activity and electrical impulses. These changes led to major defects in the emergence of brainwaves.
To correct the changes caused by the lack of the MECP2 gene, the team treated the brain organoids with 14 different drug candidates known to affect various brain cell functions. Of all the drugs tested, two stood out: nefiracetam and PHA 543613. The two drugs resolved nearly all molecular and cellular symptoms observed in the Rett syndrome “mini-brains”, with the number active neurons doubling post treatment.
The two drugs were previously tested in clinical trials for the treatment of other conditions, meaning they have been shown to be safe for human consumption.
In a news release from UC San Diego Health, Dr. Muotri stresses that although the results for the two drugs are promising, the end treatment for Rett syndrome may require a multi-drug cocktail of sorts.
“There’s a tendency in the neuroscience field to look for highly specific drugs that hit exact targets, and to use a single drug for a complex disease. But we don’t do that for many other complex disorders, where multi-pronged treatments are used. Likewise, here no one target fixed all the problems. We need to start thinking in terms of drug cocktails, as have been successful in treating HIV and cancers.”
The full results of this study were published in EMBO Molecular Medicine.
What are the latest advances in stem cell research targeting cancer? Can stem cells help people battling COVID-19 or even help develop a vaccine to stop the virus? What are researchers and the scientific community doing to help address the unmet medical needs of underserved communities? Those are just a few of the topics being discussed at the Annual CIRM Alpha Stem Cell Clinic Network Symposium on Thursday, October 8th from 9am to 1.30pm PDT.
Like pretty nearly everything these days the symposium is going to be a virtual event, so you can watch it from the comfort of your own home on a phone or laptop. And it’s free.
The CIRM Alpha Clinics are a network of leading medical centers here in California. They specialize in delivering stem cell and gene therapies to patients. So, while many conferences look at the promise of stem cell therapies, here we deal with the reality; what’s in the clinic, what’s working, what do we need to do to help get these therapies to patients in need?
It’s a relatively short meeting, with short presentations, but that doesn’t mean it will be short on content. Some of the best stem cell researchers in the U.S. are taking part so you’ll learn an awful lot in a short time.
We’ll hear what’s being done to find therapies for
Rare diseases that affect children
Type 1 diabetes
We’ll discuss how to create a patient navigation system that can address social and economic determinants that impact patient participation? And we’ll look at ways that the Alpha Clinic Network can partner with community care givers around California to increase patient access to the latest therapies.
It’s going to be a fascinating day. And did I mention it’s free!
This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved two new discovery research project as part of the $5 million in emergency funding for COVID-19 related projects. This brings the number of COVID-19 projects CIRM is supporting to 17, including three clinical trials.
$249,974 was awarded to Dr. Karen Christman at UC San Diego to develop a treatment for Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung injury that occurs when fluid leaks into the lungs and is prevalent in COVID-19 patients. Dr. Christman and her team will develop extracellular matrix (ECM) hydrogels, a kind of structure that provides support to surrounding cells. The goal is to develop a treatment that can be delivered directly to site of injury, where the ECM would recruit stem cells, treat lung inflammation, and promote lung healing.
$250,000 was awarded to Dr. Lili Yang at UCLA to develop a treatment for COVID-19. Dr. Yang and her team will use blood stem cells to create invariant natural killer T (iNKT) cells, a powerful kind of immune cell with the potential to clear virus infection and mitigate harmful inflammation. The goal is to develop these iNKT cells as an off the shelf therapy to treat patients with COVID-19.
These awards are part of CIRM’s Quest Awards Program (DISC2), which promotes promising new technologies that could be translated to enable broad use and improve patient care.
“The harmful lung inflammation caused by COVID-19 can be dangerous and life threatening,” says Maria T. Millan, M.D., the President and CEO of CIRM. “Early stage discovery projects like the ones approved today are vital in developing treatments for patients severely affected by the novel coronavirus.”
Earlier in the week the Board also approved changes to both DISC2 and clinical trial stage projects (CLIN2). These were in recognition of the Agency’s remaining budget and operational timeline and the need to launch the awards as quickly as possible.
For DISC2 awards the changes include:
Award limit of $250,000
Maximum award duration of 12 months
Initiate projects within 30 days of approval
All proposals must provide a statement describing how their overall study plan and design has considered the influence of race, ethnicity, sex and gender diversity.
All proposals should discuss the limitations, advantages, and/or challenges in developing a product or tools that addresses the unmet medical needs of California’s diverse population, including underserved communities.
Under the CLIN2 awards, to help projects carry out a clinical trial, the changes include:
Adjust award limit to the following:
Phase 1, Phase 1/2, Feasability Award Cap
Phase 2 Award Cap
Phase 3 Award Cap
Adjust the award duration to not exceed 3 years with award completion no later than November 2023
Initiate projects within 30 days of approval
All proposals must include a written plan in the application for outreach and study participation by underserved and disproportionately affected populations. Priority will be given to projects with the highest quality plans in this regard.
The changes outlined above for CLIN2 awards do not apply to sickle cell disease projects expected to be funded under the CIRM/NHLBI Cure Sickle Cell Disease joint Initiative.
Out of 100 couples in the US, around 12 or 13 will have trouble starting a family. In one third of those cases the problem is male infertility (one third is female infertility and the other third is a combination of factors). In the past treatment options for men were often limited. Now a new study out of the University of California San Diego (UCSD) could help lead to treatments to help these previously infertile men have children of their own.
The study, led by Dr. Miles Wilkinson of UCSD School of Medicine, targeted spermatogonial stem cells (SSCs), which are the cells that develop into sperm. In the past it was hard to isolate these SSCs from other cells in the testes. However, using a process called single cell RNA sequencing – which is like taking a photo of all the gene expression happening in one cell at a precise moment – the team were able to identify the SSCs.
In a news release Dr. Wilkinson, the senior author of the study, says this is a big advance on previous methods: “We think our approach — which is backed up by several techniques, including single-cell RNA-sequencing analysis — is a significant step toward bringing SSC therapy into the clinic.”
Identifying the SSCs was just the first step. Next the team wanted to find a way to be able to take those cells and grow and multiply them in the lab, an important step in having enough cells to be able to treat infertility.
So, they tested the cells in the lab and identified something called the AKT pathway, which controls cell division and survival. By blocking the AKT pathway they were able to keep the SSCs alive and growing for a month. Next they hope to build on the knowledge and expand the cells for even longer so they could be used in a clinical setting.
The hope is that this could ultimately lead to treatments for men whose bodies don’t produce sperm cells, or enough sperms cells to make them fertile. It could also help children going through cancer therapy which can destroy their ability to have children of their own later in life. By taking sperm cells and freezing them, they could later be grown and expanded in the lab and injected back into the testes to restore sperm production.
You know you are working with some of the finest scientific minds in the world when they get elected to the prestigious National Academy of Sciences (NAS). It’s the science equivalent of the baseball, football or even Rock and Roll Hall of Fame. People only get in if their peers vote them in. It’s considered one of the highest honors in science, one earned over many decades of hard work. And when it comes to hard work there are few people who work harder than U.C. San Diego’s Dr. Lawrence Goldstein, one of the newly elected members of the NAS.
For more than 25 years Larry’s work has targeted the brain and, in particular, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) better known as Lou Gehrig’s disease.
In 2012 his team was the first to create stem cell models for two different forms of Alzheimer’s, the hereditary and the sporadic forms. This gave researchers a new way of studying the disease, helping them better understand what causes it and looking at new ways of treating it.
His work has also helped develop a deeper understanding of the genetics of Alzheimer’s and to identify possible new targets for stem cell and other therapies.
Larry was typically modest when he heard the news, saying: “I have been very fortunate to have wonderful graduate students and fellows who have accomplished a great deal of excellent research. It is a great honor for me and for all of my past students and fellows – I am obviously delighted and hope to contribute to the important work of the National Academy of Sciences.”
But Larry doesn’t intend to rest on his laurels. He says he still has a lot of work to do, including “raising funding to test a new drug approach for Alzheimer’s disease that we’ve developed with CIRM support.”
Jennifer Briggs Braswell, PhD, worked with Larry at UCSD from 2005 to 2018. She says Larry’s election to the NAS is well deserved:
“His high quality publications, the pertinence of his studies in neurodegeneration to our current problems, and his constant, unwavering devotion to the next generation of scientists is matched only by his dedication to improving public understanding of science to motivate social, political, and financial support.
“He has been for me a supportive mentor, expressing enthusiastic belief in the likely success of my good ideas and delivering critique with kindness and sympathy. He continues to inspire me, our colleagues at UCSD and other communities, advocate publicly for the importance of science, and work tirelessly on solutions for neurodegenerative disorders.”
On March 19th we held a special Facebook Live “Ask the Stem Cell Team About Autism” event. We were fortunate enough to have two great experts – Dr. Alysson Muotri from UC San Diego, and CIRM’s own Dr. Kelly Shepard. As always there is a lot of ground to cover in under one hour and there are inevitably questions we didn’t get a chance to respond to. So, Dr. Shepard has kindly agreed to provide answers to all the key questions we got on the day.
If you didn’t get a chance to see the event you can watch the video here. And feel free to share the link, and this blog, with anyone you think might be interested in the material.
Can umbilical cord blood stem cells help reduce some of the symptoms?
This question was addressed by Dr. Muotri in the live presentation. To recap, a couple of clinical studies have been reported from scientists at Duke University and Sutter Health, but the results are not universally viewed as conclusive. The Duke study, which focused on very young children, reported some improvements in behavior for some of the children after treatment, but it is important to note that this trial had no placebo control, so it is not clear that those patients would not have improved on their own. The Duke team has moved forward with larger trial and placebo control.
Does it have to be the child’s own cord blood or could donated blood work too?
In theory, a donated cord product could be used for similar purposes as a child’s own cord, but there is a caveat- the donated cord tissues must have some level of immune matching with the host in order to not be rejected or lead to other complications, which under certain circumstances, could be serious.
Some clinics claim that the use of fetal stem cells can help stimulate improved blood and oxygen flow to the brain. Could that help children with autism?
Fetal stem cells have been tested in FDA approved/sanctioned clinical trials for certain brain conditions such as stroke and Parkinson Disease, where there is clearer understanding of how and which parts of the brains are affected, which nerve cells have been lost or damaged, and where there is a compelling biological rationale for how certain properties the transplanted cells, such as their anti-inflammatory properties, could provide benefit.
In his presentation, Dr. Muotri noted that neurons are not lost in autistic brains, so there is nothing that would be “replaced” by such a treatment. And although some forms of autism might include inflammation that could potentially be mitigated, it is unlikely that the degree of benefit that might come from reducing inflammation would be worth the risks of the treatment, which includes intracranial injection of donated material. Unfortunately, we still do not know enough about the specific causes and features of autism to determine if and to what extent stem cell treatments could prove helpful. But we are learning more every day, especially with some of the new technologies and discoveries that have been enabled by stem cell technology.
Some therapies even use tissue from sheep claiming that a pill containing sheep pancreas can migrate to and cure a human pancreas, pills containing sheep brains can help heal human brains. What are your thoughts on those?
For some conditions, there may be a scientific rationale for how a specific drug or treatment could be delivered orally, but this really depends on the underlying biology of the condition, the means by which the drug exerts its effect, and how quickly that drug or substance will be digested, metabolized, or cleared from the body’s circulation. Many drugs that are delivered orally do not reach the brain because of the blood-brain barrier, which serves to isolate and protect the brain from potentially harmful substances in the blood circulation. For such a drug to be effective, it would have to be stable within the body for a period of time, and be something that could exert its effects on the brain either directly or indirectly.
Sheep brain or pancreas (or any other animal tissue consumed) in a pill form would be broken down into basic components immediately by digestion, i.e. amino acids, sugars, much like any other meat or food. Often complex treatments designed to be specifically targeted to the brain are delivered by intra-cranial/intrathecal injection, or by developing special strategies to evade the blood brain barrier, a challenge that is easier said than done. For autism, there is still a lot to be learned regarding how a therapeutic intervention might work to help people, so for now, I would caution against the use of dietary supplements or pills that are not prescribed or recommended by your doctor.
What are the questions parents should ask before signing up for any stem cell therapy
These are definitely strange, unusual and challenging times. Every day seems to bring new restrictions on what we can and should do. All, of course, in the name of protecting us and helping us avoid a potentially deadly virus. We all hope this will soon pass but we also know the bigger impact of the coronavirus is likely to linger for many months, perhaps even years.
With that in mind a few people have asked us why we are still going ahead with our Facebook Live ‘Ask the Stem Cell Team About Autism’ event this Thursday, March 19th at 12pm PDT. It’s a good question. And the answer is simple. Because there is still a need for good, thoughtful information about the potential for stem cells to help families who have a loved one with autism. And because we still need to do all we can to dispel the bad information out there and warn people about the bogus clinics offering unproven therapies.
In many ways Facebook Live is the perfect way to deliver this information. It allows us to reach out to large numbers of people without having them in the same room. We can educate not contaminate.
And we have some great experts to discuss the use of stem cells in helping people with autism.
The event features Dr. Alysson Muotri from UC San Diego. We have written about his work with stem cells for autism in the past. And CIRM’s own Associate Director for Discovery and Translation, Dr. Kelly Shepard.
But we also want you to be a part of this as well. So, join us online for the event. You can post comments and questions during the event, and we’ll do our best to answer them. Or you can send us in questions ahead of time to email@example.com.
If you were unable to tune in while we were live, not to worry, you you can watch it here on our Facebook page
A CIRM-funded trial conducted by Oncternal Therapeutics in collaboration with UC San Diego released an interim clinical data update for patients with mantle cell lymphoma (MCL), a type of blood cancer.
The treatment being developed involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the blood cancer and makes it more vulnerable to anti-cancer drugs.
Here are the highlights from the new interim clinical data:
Patients had received a median of two prior therapies before participating in this study including chemotherapy; autologous stem cell transplant (SCT); autologous SCT and CAR-T therapy; autologous SCT and allogeneic SCT; and ibrutinib with rituximab, a different type of antibody therapy.
6 of the 12 patients in the trial experienced a Complete Response (CR), which is defined as the disappearance of all signs of cancer in response to treatment.
All six CRs are ongoing, including one patient who has remained in CR for more than 21 months past treatment.
Four of the six patients achieved CRs within four months on the combination of cirmtuzumab and ibrutinib.
Of the remaining 6 patients, 4 experienced a Partial Response (PR), which is defined as a decrease in the extent of the cancer in the body.
The remaining two patients experienced Stable Disease (SD), which is defined as neither an increase or decrease in the extent of the cancer.
The full interim clinical data update can be viewed in the press release here.