Our 2021-22 Annual Report is now online. It’s filled with information about the work we have done over the last year (we are on a fiscal calendar year from July 1 – June 30), the people who have helped us do that work, and some of the people who have benefited from that work. One of those is Dr. Alysson Muotri, a professor in the Departments of Pediatrics and Cellular & Molecular Medicine at the University of California, San Diego.
For Dr. Alysson Muotri, trying to unlock the secrets of the brain isn’t just a matter of scientific curiosity, it’s personal. He has a son with autism and Dr. Muotri is looking for ways to help him, and millions of others like him around the world.
He created the Tooth Fairy project where parents donated more than 3,000 baby teeth from children with autism and children who are developing normally. Dr. Muotri then turned cells from those teeth into neurons, the kind of brain cell affected by autism. He is using those cells to try and identify how the brain of a child with autism differs from a child who is developing normally.
“We’ve been using cells from this population to see what are the alterations (in the gene) and if we can revert them back to a normal state. If you know the gene that is affected, and autism has a strong genetic component, by genome sequencing you can actually find what are the genes that are affected and in some cases there are good candidates for gene therapy. So, you just put the gene back. And we can see that in the lab where we are correcting the gene that is mutated, the networks start to function in a way that is more neurotypical or normal. We see that as highly promising, there’s a huge potential here to help those individuals.”
He is also creating brain organoids, three-dimensional structures created from stem cells that mimic some of the actions and activities of the brain. Because these are made from human cells, not mice or other animals, they may be better at indicating if new therapies have any potential risks for people.
“We can test drugs in the brain organoids of the person and see if it works, see if there’s any toxicity before you actually give the drug to a person, and it will save us time and money and will increase our knowledge about the human brain.”
He says he still gets excited seeing how these cells work. “It’s amazing, it’s a miracle. Every time I see it, it’s like seeing dolphins in the sea because it’s so beautiful.”
Dr. Muotri is also a big proponent of diversity, equity and inclusion in scientific research. He says in the past it was very much a top-down model with scientists deciding what was important. He says we need to change that and give patients and communities a bigger role in shaping the direction of research.
“I think this is something we scientists have to learn, how to incorporate patients in our research. These communities are the ones we are studying, and we need to know what they want and not assume that what we want is what they want. They should be consulted on our grants, and they should participate in the design of our experiments. That is the future.”
Normally if you meet someone who has a mini-fridge filled with brains, your first thought is to call the police. But when that someone is Dr. Alysson Muotri, a professor at U.C. San Diego, your second thought is “do tell me more.”
Alysson is a researcher who is fascinated by the human brain. He is working on many levels to try and unlock its secrets and give us a deeper understanding of how our brains evolved and how they work.
One of the main focuses of his work is autism (he has a son on the autism spectrum) and he has found a way to see what is happening inside the cells affected by autism—work that is already leading to the possibility of new treatments.
As for those mini-brains in his lab? Those are brain organoids, clumps of neurons and other cells that resemble—on a rudimentary level—our brains. They are ideal tools for seeing how our brains are organized, how the different cells signal and interact with each other. He’s already sent some of these brain organoids into space.
Alysson talks about all of this, plus how our brains compare to those of Neanderthals, on the latest episode of our podcast, Talking ‘Bout (re)Generation.
Alzheimer’s is a progressive disease that destroys memory and other important mental functions. According to the non-profit HFC, co-founded by CIRM Board member Lauren Miller Rogen and her husband Seth Rogen, more than 5 million Americans are living with Alzheimer’s. It is the 6th leading cause of death in the U.S and it is estimated that by 2050 as many as 16 million Americans will have the disease. Alzheimer’s is the only cause of death among the top 10 in the U.S. without a way to prevent, cure, or even slow its progression, which is it is crucial to better understand the disease and to develop and test potential treatments.
It is precisely for this reason that researchers led by Yanhong Shi, Ph.D. at City of Hope have developed a ‘mini-brain’ model using stem cells in order to study Alzheimer’s and to test drugs in development.
The team was able to model sporadic Alzheimer’s, the most common form of the disease, by using human induced pluripotent stem cells (iPSCs), a kind of stem cell that can be created from skin or blood cells of people through reprogramming and has the ability to turn into virtually any other kind of cell. The researchers used these iPSCs to create ‘mini-brains’, also known as brain organoids, which are 3D models 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 physical structure and other characteristics.
The scientists exposed the ‘mini-brains’ to serum that mimics age-associated blood-brain barrier (BBB) breakdown. The BBB is a protective barrier that surrounds the brain and its breakdown has been associated with Alzheimer’s and other age-related neurodegenerative diseases . After exposure, the team tested the ‘mini-brains’ for various Alzheimer’s biomarkers. These markers included elevated levels of proteins known as amyloid and tau that are associated with the disease and synaptic breaks linked to cognitive decline.
Research using brain organoids has shown that exposure to serum from blood could induce multiple Alzheimer’s symptoms. This suggests that combination therapies targeting multiple areas would be more effective than single-target therapies currently in development.
The team found that attempting a single therapy, such as inhibiting only amyloid or tau proteins, did not reduce the levels of tau or amyloid, respectively. These findings suggest that amyloid and tau likely cause disease progression independently. Furthermore, exposure to serum from blood, which mimics BBB breakdown, could cause breaks in synaptic connections that help brains remember things and function properly.
In a press release from the Associated Press, Dr. Shi elaborated on the importance of their model for studying Alzheimer’s.
“Drug development for Alzheimer’s disease has run into challenges due to incomplete understanding of the disease’s pathological mechanisms. Preclinical research in this arena predominantly uses animal models, but there is a huge difference between humans and animals such as rodents, especially when it comes to brain architecture. We, at City of Hope, have created a miniature brain model that uses human stem cell technology to study Alzheimer’s disease and, hopefully, to help find treatments for this devastating illness.”
The full results of this study were published in Advance Science.
Dementia is a general term that describes a set of diseases that impair the ability to remember, think, or make decisions that interfere with doing everyday activities. According to the World Health Organization (WHO), around 50 million people worldwide have dementia with nearly 10 million new cases every year. Although it primarily affects older people it is not a normal part of aging. As our population ages its critical to better understand why this occurs.
Frontotemporal dementia is a rare form of dementia where people start to show signs between the ages of 40 and 60. It affects the front and side (temporal) areas of the brain, hence the name. It leads to behavior changes and difficulty with speaking and thinking. This form of the disease is caused by a genetic mutation called tau, which is known to be associated with Alzheimer’s disease and other dementias.
A CIRM supported study using induced pluripotent stem cells (iPSCs) led by Kathryn Bowles, Ph.D. and conducted by a team of researchers at Mount Sinai were able to recreate much of the damage seen in a widely studied form of the frontotemporal dementia by growing special types of ‘mini-brains’, also known as cerebral organoids.
iPSCs are a kind of stem cell that can be created from skin or blood cells through reprogramming and have the ability to turn into virtually any other kind of cell. The team used iPSCs to create thousands of tiny, 3D ‘mini-brains’, which mimic the early growth and development of the brain.
The researchers examined the growth and development of these ‘mini-brains’ using stem cells derived from three patients, all of whom carried a mutation in tau. They then compared their results with those observed in “normal” mini-brains which were derived from patient stem cells in which the disease-causing mutation was genetically corrected.
After six months, signs of neurodegeneration were seen in the patient ‘mini-brains’. The patient-derived ‘mini-brains’ had fewer excitatory neurons compared to the “normal” ones which demonstrates that the tau mutation was sufficient to cause higher levels of cell death of this specific class of neurons. Additionally, the patient-derived ‘mini-brains’ also had higher levels of harmful versions of tau protein and elevated levels of inflammation.
In a news release from Mount Sinai, Dr. Bowles elaborated on the results of this study.
“Our results suggest that the V337M mutant tau sets off a vicious cycle in the brain that puts excitatory neurons under great stress. It hastens the production of new proteins needed for maturation but prevents disposal of the proteins that are being replaced.”
Since the start of the coronavirus pandemic early last year, scientists all over the world are still trying to better understand SARS-CoV-2, the virus that causes COVID-19. Although the more commonly known symptoms involve respiratory issues, there have been other long term problems observed in recovered patients. These consist of heart issues, fatigue, and neurological issues such as loss of taste and smell and “brain fog”.
To better understand this, Dr. Tariq Rana and a team of researchers at the UC San Diego School of Medicine are using stem cells to create lung and brain organoids to better understand how the virus interacts with the various organ systems and to better develop therapies that block infection. Organoids are 3D models made of cells that can be used to analyze certain features of the human organ being modeled. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics.
The team’s lung and brain organoids produced molecules ACE2 and TMPRSS2, which sit like doorknobs on the outer surfaces of cells. SARS-CoV-2 is able to use these doorknobs to enter cells and establish infection.
Dr. Rana and his team then developed a pseudovirus, a noninfectious version of SARS-CoV-2, and attached a fluorescent label, allowing them to measure how effectively the virus binds in human lung and brain organoids as well as to evaluate the cells’ response. The team was surprised to see an approximately 10-fold higher SARS-CoV-2 infection in lung organoids compared to brain organoids. Additionally, treatment with TMPRSS2 inhibitors reduced infection levels in both organoids.
Besides differences in infection levels, the lung and brain organoids also differed in their responses to the virus. Infected lung organoids pumped out molecules intended to summon help from the immune system while infected brain organoids upped their production of molecules that plays a fundamental role in pathogen recognition and activation of the body’s own immune defenses.
In a news release from UC San Diego Health, Dr. Rana elaborates on the results of his study.
“We’re finding that SARS-CoV-2 doesn’t infect the entire body in the same way. In different cell types, the virus triggers the expression of different genes, and we see different outcomes.”
The next steps for Rana and his team is to develop SARS-CoV-2 inhibitors and test out how well they work in organoid models derived from people of a variety of racial and ethnic backgrounds that represent California’s diverse population. To carry out this research, CIRM awarded Dr. Rana a grant of $250,000, which is part of the $5 million in emergency funding for COVID-19 research that CIRM authorized at the beginning of the pandemic.
The evolution of modern day humans has always been a topic that has been shrouded in mystery. Some of what is known is that Neanderthals, an archaic human species that lived on this planet up until about 11,700 years ago, interbred with our species (Homo sapiens) at some point in time. Although their brains were about as big as ours, anthropologists think they must have worked differently due to the fact that they never achieved the sophisticated technology and artistry modern humans have.
Since brains do not fossilize, it has been challenging to see how these two early human species have changed over time. To help answer this question, Dr. Alysson Muotri and his team at UC San Diego created so-called “mini-brains” using stem cells and gene editing technology to better understand how the Neanderthal brain might have functioned.
For this study, Dr. Muotri and his team closely evaluated the differences in genes between modern day humans and Neanderthals. They found a total of 61 different genes, but for this study focused on one in particular that plays a role in influencing early brain development.
Using gene editing technology, the team introduced the Neanderthal version of the gene into human stem cells. These stem cells, which have the ability to become various cell types, were then used to create brain cells. These cells eventually formed brain organoids or “mini-brains”, 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 physical structure and other characteristics. In a previous CIRM funded study, Dr. Muotri had used “mini-brains” to model an autism spectrum disorder and help test treatments.
Dr. Muotri and his team found that the Neanderthal-like brain organoids looked very different than modern human brain organoids, having a distinctly different shape. Upon further analysis, the team found that modern and Neanderthal-like brain organoids also differed in the way their cells grow. Additionally, the way in which connections between neurons formed as well as the proteins involved in forming these connections differed between the two organoids. Finally, electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-like brain organoids.
According to Muotri, the neural network changes in Neanderthal-like brain organoids mimic the way newborn primates acquire new abilities more rapidly than human newborns.
In a news release from UCSD, Dr. Muotri discusses the next steps in advancing this research.
“This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered. We’re looking forward to this new combination of stem cell biology, neuroscience and paleogenomics.”
All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.
It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19. In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus. One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.
It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grantand $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center. The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.
At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain. Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.
The team first created neurons and astrocytes. Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them. The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients. The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.
Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain. They were able to create two different organoid models: one that contained astrocytes and one without them. They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model.
The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2. They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient. Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4. Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral. The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.
The results were astounding. The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes. Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes.
“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”
In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes. They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death. For neurons, it was able to rescue them from steadily losing their function and even dying.
The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19. Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after.
“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami. “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”
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.
A few weeks ago we held a Facebook Live “Ask the Stem Cell Team About Parkinson’s Disease” event. As you can imagine we got lots of questions but, because of time constraints, only had time to answer a few. Thanks to my fabulous CIRM colleagues, Dr. Lila Collins and Dr. Kent Fitzgerald, for putting together answers to some of the other questions. Here they are.
Q:It seems like we have been hearing for years that stem cells can help people with Parkinson’s, why is it taking so long?
A: Early experiments in Sweden using fetal tissue did provide a proof of concept for the strategy of replacing dopamine producing cells damaged or lost in Parkinson’s disease (PD) . At first, this seemed like we were on the cusp of a cell therapy cure for PD, however, we soon learned based on some side effects seen with this approach (in particular dyskinesias or uncontrollable muscle movements) that the solution was not as simple as once thought.
While this didn’t produce the answer it did provide some valuable lessons.
The importance of dopaminergic (DA) producing cell type and the location in the brain of the transplant. Simply placing the replacement cells in the brain is not enough. It was initially thought that the best site to place these DA cells is a region in the brain called the SN, because this area helps to regulate movement. However, this area also plays a role in learning, emotion and the brains reward system. This is effectively a complex wiring system that exists in a balance, “rewiring” it wrong can have unintended and significant side effects.
Another factor impacting progress has been understanding the importance of disease stage. If the disease is too advanced when cells are given then the transplant may no longer be able to provide benefit. This is because DA transplants replace the lost neurons we use to control movement, but other connected brain systems have atrophied in response to losing input from the lost neurons. There is a massive amount of work (involving large groups and including foundations like the Michael J Fox Foundation) seeking to identify PD early in the disease course where therapies have the best chance of showing an effect. Clinical trials will ultimately help to determine the best timing for treatment intervention.
Ideally, in addition to the cell therapies that would replace lost or damaged cells we also want to find a therapy that slows or stops the underlying biology causing progression of the disease.
So, I think we’re going to see more gene therapy trials including those targeting the small minority of PD that is driven by known mutations. In fact, Prevail Therapeutics will soon start a trial in patients with GBA1 mutations. Hopefully, replacing the enzyme in this type of genetic PD will prevent degeneration.
And, we are also seeing gene therapy approaches to address forms of PD that we don’t know the cause, including a trial to rescue sick neurons with GDNF which is a neurotrophic factor (which helps support the growth and survival of these brain cells) led by Dr Bankiewicz and trials by Axovant and Voyager, partnered with Neurocrine aimed at restoring dopamine generation in the brain.
A small news report came out earlier this year about a recently completed clinical trial by Roche Pharma and Prothena. This addressed the build up in the brain of what are called lewy bodies, a problem common to many forms of PD. While the official trial results aren’t published yet, a recent press release suggests reason for optimism. Apparently, the treatment failed to statistically improve the main clinical measurement, but other measured endpoints saw improvement and it’s possible an updated form of this treatment will be tested again in the hopes of seeing an improved effect.
Finally, I’d like to call attention to the G force trials. Gforce is a global collaborative effort to drive the field forward combining lessons learned from previous studies with best practices for cell replacement in PD. These first-in-human safety trials to replace the dopaminergic neurons (DANs) damaged by PD have shared design features including identifying what the best goals are and how to measure those.
And the Summit PD trial, Dr Jeanne Loring of Aspen Neuroscience.
Taken together these should tell us quite a lot about the best way to replace these critical neurons in PD.
As with any completely novel approach in medicine, much validation and safety work must be completed before becoming available to patients
The current approach (for cell replacement) has evolved significantly from those early studies to use cells engineered in the lab to be much more specialized and representing the types believed to have the best therapeutic effects with low probability of the side effects (dyskinesias) seen in earlier trials.
If we don’t really know the cause of Parkinson’s disease, how can we cure it or develop treatments to slow it down?
PD can now be divided into major categories including 1. Sporadic, 2. Familial.
For the sporadic cases, there are some hallmarks in the biology of the neurons affected in the disease that are common among patients. These can be things like oxidative stress (which damages cells), or clumps of proteins (like a-synuclein) that serve to block normal cell function and become toxic, killing the DA neurons.
The second class of “familial” cases all share one or more genetic changes that are believed to cause the disease. Mutations in genes (like GBA, LRRK2, PRKN, SNCA) make up around fifteen percent of the population affected, but the similarity in these gene mutations make them attractive targets for drug development.
CIRM has funded projects to generate “disease in a dish” models using neurons made from adults with Parkinson’s disease. Stem cell-derived models like this have enabled not only a deep probing of the underlying biology in Parkinson’s, which has helped to identify new targets for investigation, but have also allowed for the testing of possible therapies in these cell-based systems.
iPSC-derived neurons are believed to be an excellent model for this type of work as they can possess known familial mutations but also show the rest of the patients genetic background which may also be a contributing factor to the development of PD. They therefore contain both known and unknown factors that can be tested for effective therapy development.
I have heard of scientists creating things called brain organoids, clumps of brain cells that can act a little bit like a brain. Can we use these to figure out what’s happening in the brain of people with Parkinson’s and to develop treatments?
There is considerable excitement about the use of brain organoids as a way of creating a model for the complex cell-to-cell interactions in the brain. Using these 3D organoid models may allow us to gain a better understanding of what happens inside the brain, and develop ways to treat issues like PD.
The organoids can contain multiple cell types including microglia which have been a hot topic of research in PD as they are responsible for cleaning up and maintaining the health of cells in the brain. CIRM has funded the Salk Institute’s Dr. Fred Gage’s to do work in this area.
If you go online you can find lots of stem cells clinics, all over the US, that claim they can use stem cells to help people with Parkinson’s. Should I go to them?
In a word, no! These clinics offer a wide variety of therapies using different kinds of cells or tissues (including the patient’s own blood or fat cells) but they have one thing in common; none of these therapies have been tested in a clinical trial to show they are even safe, let alone effective. These clinics also charge thousands, sometimes tens of thousands of dollars these therapies, and because it’s not covered by insurance this all comes out of the patient’s pocket.
These predatory clinics are peddling hope, but are unable to back it up with any proof it will work. They frequently have slick, well-designed websites, and “testimonials” from satisfied customers. But if they really had a treatment for Parkinson’s they wouldn’t be running clinics out of shopping malls they’d be operating huge medical centers because the worldwide need for an effective therapy is so great.
Here’s a link to the page on our website that can help you decide if a clinical trial or “therapy” is right for you.
Is it better to use your own cells turned into brain cells, or cells from a healthy donor?
This is the BIG question that nobody has evidence to provide an answer to. At least not yet.
Let’s start with the basics. Why would you want to use your own cells? The main answer is the immune system. Transplanted cells can really be viewed as similar to an organ (kidney, liver etc) transplant. As you likely know, when a patient receives an organ transplant the patient’s immune system will often recognize the tissue/organ as foreign and attack it. This can result in the body rejecting what is supposed to be a life-saving organ. This is why people receiving organ transplants are typically placed on immunosuppressive “anti-rejection “drugs to help stop this reaction.
In the case of transplanted dopamine producing neurons from a donor other than the patient, it’s likely that the immune system would eliminate these cells after a short while and this would stop any therapeutic benefit from the cells. A caveat to this is that the brain is a “somewhat” immune privileged organ which means that normal immune surveillance and rejection doesn’t always work the same way with the brain. In fact analysis of the brains collected from the first Swedish patients to receive fetal transplants showed (among other things) that several patients still had viable transplanted cells (persistence) in their brains.
Transplanting DA neurons made from the patient themselves (the iPSC method) would effectively remove this risk of the immune system attack as the cells would not be recognized as foreign.
CIRM previously funded a discovery project with Jeanne Loring from Scripps Research Institute that sought to generate DA neurons from Parkinson’s patients for use as a potential transplant therapy in these same patients. This project has since been taken on by a company formed, by Dr Loring, called Aspen Neuroscience. They hope to bring this potential therapy into clinical trials in the near future.
A commonly cited potential downside to this approach is that patients with genetic (familial) Parkinson’s would be receiving neurons generated with cells that may have the same mutations that caused the problem in the first place. However, as it can typically take decades to develop PD, these cells could likely function for a long time. and prove to be better than any current therapies.
Creating cells from each individual patient (called autologous) is likely to be very expensive and possibly even cost-prohibitive. That is why many researchers are working on developing an “off the shelf” therapy, one that uses cells from a donor (called allogeneic)would be available as and when it’s needed.
When the coronavirus happened, it seemed as if overnight the FDA was approving clinical trials for treatments for the virus. Why can’t it work that fast for Parkinson’s disease?
While we don’t know what will ultimately work for COVID-19, we know what the enemy looks like. We also have lots of experience treating viral infections and creating vaccines. The coronavirus has already been sequenced, so we are building upon our understanding of other viruses to select a course to interrupt it. In contrast, the field is still trying to understand the drivers of PD that would respond to therapeutic targeting and therefore, it’s not precisely clear how best to modify the course of neurodegenerative disease. So, in one sense, while it’s not as fast as we’d like it to be, the work on COVID-19 has a bit of a head start.
Much of the early work on COVID-19 therapies is also centered on re-purposing therapies that were previously in development. As a result, these potential treatments have a much easier time entering clinical trials as there is a lot known about them (such as how safe they are etc.). That said, there are many additional therapeutic strategies (some of which CIRM is funding) which are still far off from being tested in the clinic.
The concern of the Food and Drug Administration (FDA) is often centered on the safety of a proposed therapy. The less known, the more cautious they tend to be.
As you can imagine, transplanting cells into the brain of a PD patient creates a significant potential for problems and so the FDA needs to be cautious when approving clinical trials to ensure patient safety.
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