Reversing Effects of Autism Linked Mutation in Brain Organoids
Published: 2022-05-05 - Updated: 2022-10-08
Author: University of California San Diego School of Medicine | Contact: ucsd.edu
Peer-Reviewed Publication: N/A
Library: Autism Information Publications
Synopsis: UC San Diego study reveals gene therapy reverses the effects of autism-linked mutation in brain organoids by using lab-grown human brain tissue to identify neural abnormalities in Pitt-Hopkins Syndrome and test gene therapy tools. Several neurological and neuropsychiatric diseases, including autism spectrum disorders (ASD) and schizophrenia, have been linked to mutations in Transcription Factor 4 (TCF4), an essential gene in brain development. The team tested two gene therapy strategies for recovering the functional gene in brain tissue. Both methods effectively increased TCF4 levels and, in doing so, corrected Pitt-Hopkins Syndrome phenotypes at molecular, cellular, and electrophysiological scales.
An organoid is a tiny, self-organized three-dimensional tissue culture derived from stem cells. Such cultures can be crafted to replicate much of an organ's complexity or express selected aspects, like producing only certain types of cells. Organoids are derived from one or a few cells from a tissue, embryonic stem cells, or induced pluripotent stem cells, which can self-organize in three-dimensional culture owing to their self-renewal and differentiation capacities. Brain organoids display structures that resemble defined brain regions and simulate specific changes in neurological disorders; thus, organoids have become an excellent model for investigating brain development, neurological diseases, and reversing effects of autism-linked mutation. To date, researchers have produced organoids that resemble the brain, kidney, lung, intestine, stomach, and liver, and many more are on the way.
In a study published May 02, 2022, in Nature Communications, scientists at University of California San Diego School of Medicine used human brain organoids to reveal how a genetic mutation associated with a profound form of autism disrupts neural development. Using gene therapy tools to recover the gene's function effectively rescued neural structure and function.
Several neurological and neuropsychiatric diseases, including autism spectrum disorders (ASD) and schizophrenia, have been linked to mutations in Transcription Factor 4 (TCF4), an essential gene in brain development. Transcription factors regulate when other genes are turned on or off, so their presence, or lack thereof, can have a domino effect in the developing embryo. Still, little is known about what happens to the human brain when TCF4 is mutated.
To explore this question, researchers focused on Pitt-Hopkins Syndrome, an ASD specifically caused by mutations in TCF4. Children with the genetic condition have profound cognitive and motor disabilities and are typically non-verbal.
Existing mouse models of Pitt-Hopkins Syndrome fail to mimic patients' neural characteristics accurately, so the UC San Diego team created a human research model of the disorder instead. Using stem cell technology, they converted patients' skin cells into stem cells, which were then developed into three-dimensional brain organoids, or "mini-brains."
Initial observations of the brain organoids revealed a slew of structural and functional differences between the TCF4-mutated samples and their controls.
"Even without a microscope, you could tell which brain organoid had the mutation," said senior study author Alysson R. Muotri, Ph.D., professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program and member of the Sanford Consortium for Regenerative Medicine.
The TCF4-mutated organoids were substantially smaller than normal organoids, and many cells were not neurons but neural progenitors. These simple cells are meant to multiply and then mature into specialized brain cells, but in the mutated organoids, some part of this process had gone awry.
A series of experiments revealed that the TCF4 mutation led to downstream dysregulation of SOX genes and the Wnt pathway, two important molecular signals that guide embryonic cells to multiply, mature into neurons, and migrate to the correct location in the brain.
Due to this dysregulation, neural progenitors did not multiply efficiently, thus producing fewer cortical neurons. The cells that matured into neurons were less excitable than normal and often remained clustered instead of arranging themselves into finely tuned neural circuits.
This atypical cellular architecture disrupted the flow of neural activity in the mutated brain organoid, which authors said would likely contribute to impaired cognitive and motor function down the line.
"We were surprised to see such major developmental issues at all these different scales, and it left us wondering what we could do to address them," said first author Fabio Papes, Ph.D., associate professor at the University of Campinas and visiting scholar at UC San Diego School of Medicine, who jointly supervised the work with Muotri. Papes has a relative with Pitt-Hopkins Syndrome, which motivated him to study TCF4.
The team tested two gene therapy strategies for recovering the functional gene in brain tissue. Both methods effectively increased TCF4 levels and, in doing so, corrected Pitt-Hopkins Syndrome phenotypes at molecular, cellular, and electrophysiological scales.
"The fact that we can correct this one gene and the entire neural system reestablishes itself, even at a functional level, is amazing," said Muotri.
Muotri notes that these genetic interventions occurred at a prenatal stage of brain development. In contrast, children receive their diagnosis and treatment a few years later in a clinical setting. Thus, clinical trials must first confirm whether a later intervention is still safe and effective. The team is currently optimizing their recently licensed gene therapy tools in preparation for such a trial, where spinal injections of the genetic vector would hopefully recover TCF4 function in the brain.
"For these children and their loved ones, any improvements in motor-cognitive function and quality of life would be worth the try," Muotri said.
"What is truly outstanding about this work is that these researchers are going beyond the lab and working hard to make these findings translatable to the clinic," said Audrey Davidow, president of the Pitt Hopkins Research Foundation. "This is so much more than a stellar academic paper; it's a true measure of what well-practiced science can accomplish to change human lives for the better, hopefully."
About the Study
Janaina S. de Souza, Ryan A. Szeto, Erin LaMontagne, Simoni H. Avansini, Sandra M. Sanchez-Sanchez, Wei Wu, Hang Yao and Gabriel Haddad of UC San Diego; Antonio P. Camargo, Vinicius M. A. Carvalho, Jose R. Teixeira, Thiago S. Nakahara, Carolina N. Santo, Barbara M. P. Araujo and Paulo E. N. F. Velho at the University of Campinas.
This work was funded, in part, by the National Institutes of Health (grant R01 MH123828), the Pitt Hopkins Research Foundation, and the São Paulo Research Foundation (grants 2020/11451-7, 2018/03613-7, 2018/04240-0) and the U.S. Department of Energy Joint Genome Institute (DE-AC02-05CH11231).
Alysson R. Muotri is the co-founder of and has an equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis.
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