April is National Autism Awareness Month and people and organizations around the world trying to both raise awareness and understand autism, which affects more than 20 million people globally. Autism affects early brain development and causes a wide spectrum of social, mental, physical and emotional symptoms that appear during childhood. Because the symptoms and their severity can vary extremely between people, scientists now use the classification of autism spectrum disorder (ASM).
In celebration of Autism Awareness Month, we’re featuring an interview with a CIRM-funded scientist who is on the forefront of autism and ASD research. Dr. Alysson Muotri is a professor at UC San Diego and his lab is interested in unlocking the secrets to brain development by using molecular tools and stem cell models.
One of his main research projects is on autism. Scientists in his lab are using induced pluripotent stem cells (iPSCs) derived from individuals with ASD to model the disease in a dish. From these stem cell models, his team is identifying genes that are associated with ASD and potential drugs that could be used to treat this disorder. Ultimately, Dr. Muotri’s goal is to pave a path for the development of personalized therapies for people with ASD.
I reached out to Dr. Muotri to ask for an update on his Autism research. His responses are below.
Q: Can you briefly summarize your lab’s work on Autism Spectrum Disorders?
AM: As a neuroscientist studying autism, I was frustrated with the lack of a good experimental model to understand autism. All the previous models (animal, postmortem brain tissues, etc.) have serious experimental limitations. The inaccessibility of the human brain has blocked the progress of research on ASD for a long time. Cellular reprogramming allows us to transform easy-access cell types (such as skin, blood, dental pulp, etc.) into brain cells or even “mini-brains” in the lab. Because we can capture the entire genome of the person, we can recapitulate early stages of neurodevelopment of that same individual. This is crucial to study neurodevelopment disorders, such as ASD, because of the strong genetic factor underlying the pathology [the cause of a disease]. By comparing “mini-brains” between an ASD and neurotypical [non-ASD] groups, we can find anatomical and functional differences that might explain the clinical symptoms.
Q: What types of tools and models are you using to study ASD?
AM: Most of my lab takes advantage of reprogramming stem cells and genome editing techniques to generate 3D organoid models of ASD. We use the stem cells to create brain organoids, also called “mini-brains” in the lab. These mini-brains will develop from single cells and grow and mature in the same way as the fetal brain. Thus, we can learn about their structure and connectivity over time.
This new model brings something novel to the table: the ability to experimentally test specific hypotheses in a human background. For example, we can ask if a specific genetic variant is causal for an autistic individual. Thus, we can edit the genome of that autistic individual, fixing target mutations in these mini-brains and check if now the fixed mini-brains will develop any abnormalities seen in ASD.
The ability to combine all these recent technologies to create a human experimental model of ASD in the lab is quite new and very exciting. As with any other model, there are limitations. For example, the mini-brains don’t have all the complexity and cell types seen in the developing human embryo/fetus. We also don’t know exactly if we are giving them the right and necessary environment (nutrients, growth factors, etc.) to mature. Nonetheless, the progress in this field is taking off quickly and it is all very promising.
Q: We’ve previously written about your lab’s work on the Tooth Fairy Project and how you identified the TRPC6 gene. Can you share updates on this project and any new insights?
AM: The Tooth Fairy Project was designed to collect dental pulp cells from ASD and control individuals in a non‑invasive way, with no need for skin biopsies or blood draws. To reach families, we used social media to connect and engage them in our research. As a result, the project was extremely successful, and we now have hundreds of cell samples in the lab. We use this material to reprogram cells into stem cells and to sequence their DNA.
One early ASD participant carried a mutation in one copy of the TRPC6 gene, a new ASD gene candidate. Everyone has two copies of this gene, but because of the mutation, this child has only one functional copy. Using stem cells, we recreated cortical neurons from this individual and confirmed that the mutation reduces the formation of excitatory synapses—connections needed to transmit information.
Interestingly, while studying TRPC6, we found that hyperforin, a molecule in St. John’s Wort, can stimulate functional TRPC6. Because the child still had one working gene copy, it made sense to test whether hyperforin could compensate for the mutated one. It did. After only two weeks of hyperforin treatment, the neurons derived from this autistic boy showed restored function. Even more encouraging, the family agreed to add St. John’s Wort to his diet, and we have anecdotal evidence that his social and emotional skills improved.
To me, this is the first example of personalized treatment for ASD—starting with genome sequencing, identifying causative mutations, modeling the biology in the lab, and moving toward clinical impact. I believe many other autistic individuals could benefit from this approach, even with repurposed or over‑the‑counter medications. That insight, to me, is the most exciting.
Watch Dr. Muotri’s Spotlight presentation about the Tooth Fairy Project and his work on autism.
Q: Is any of the research you are currently doing in autism moving towards clinical trials?
AM: IGF‑1, or insulin growth factor‑1, is a drug we identified as promising for Rett syndrome and for a subgroup of idiopathic ASD. As a result, it is now in clinical trials. In addition, we recently completed a CIRM‑funded large‑scale drug screen for ASD. The early data is very promising, with several strong candidates.
At this point, we have 14 drugs in the pipeline, including some repurposed cancer drugs that may also work for ASD. However, we will need additional preclinical studies before moving any of them into clinical trials.
Q: What do you think the future of diagnosis and treatment will be for patients with ASD?
AM: I am a strong supporter of personalized treatments for ASD. While we continue searching for therapies that help many people with ASD, we also recognize that some cases may be easier to address based on their genetic profile. For this reason, using stem cells to create “brain avatars” of individuals with ASD in the lab is very exciting.
In addition, we are studying whether this approach could serve as a future diagnostic tool for ASD. I can imagine every baby having a lab‑generated “brain avatar,” allowing us to spot early “red flags” in children who fail to meet neurodevelopmental milestones. If we can identify these cases long before symptoms appear, then we could start early treatments and therapies, increasing the chances of a better prognosis and clinical path.
Ultimately, none of this would be possible without stem cell research.
Q: What other types of research is your lab doing?
AM: My lab is also using these human mini‑brains to test how environmental factors affect neurodevelopment. For example, by exposing the mini‑brains to pollution particles, household chemicals, cosmetics, or pesticides, we can measure the concentrations likely to cause brain abnormalities such as defects in neuronal migration or synaptogenesis. In this way, the toxicology test can complement or even replace traditional analyses, such as animal models, which are neither humane nor reliably predictive of human biology.
A clear example from my lab came with the Zika virus. Using this approach, we confirmed the virus’s detrimental effect on brain development. Not only did we show a direct link between the Brazilian Zika strain and microcephaly, but our data also revealed a potential mechanism: the virus kills neural progenitor cells, reducing the thickness of the brain’s cortical layers.).
You can learn more about Dr. Muotri’s research on his lab’s website.