Scientists reverse effects of autism-linked mutation with gene therapy

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Using human brain organoids, researchers at the University of California (UC) San Diego School of Medicine uncovered the mechanisms behind how a genetic mutation associated with autism disrupts neural development, and used gene therapy to recover the gene’s function, according to a new study.

The study was published in Nature Communications, and was led by Alysson Muotri, PhD, professor at UC San Diego School of Medicine and director of the UC San Diego Stem Cell Program. The mutation studied is in Transcription Factor 4 (TCFA), a gene that contributes to brain development, according to the study’s authors. Mutations in the TCFA gene have been linked to several neurological and neuropsychiatric diseases, among them are autism spectrum disorders (ASD) and schizophrenia.

The study’s researchers set out to discover more about how a mutation in TCF4 effects the brain. To do so, researchers focused on an ASD called Pitt-Hopkins Syndrome, which is caused by mutations in TCF4. Using stem cell technology, researchers converted patients’ skin cells into stem cells, which were later turned into “mini brains,” also called brain organoids.

When scientist compared the brain organoids with the TCF4 mutation to normal organoids, they found several structural and functional differences. According to the researchers, the mutated organoids had atypical cellular architecture which interrupted the flow of neural activity, likely leading to impaired cognitive and motor function.

The team then conducted two different forms of gene therapies on the brain tissue. Both methods increased productions of TCF4 and corrected Pitt Hopkins Syndrome at the molecular, cellular, and electrophysiological level.

“The fact that we can correct this one gene and the entire neural system reestablishes itself, even at a functional level, is amazing,” Muotri said in a statement.

Although this study includes promising evidence that gene therapy can reverse this TCF4 mutation, according to the study’s authors, more research must be done before any conclusions on the effectiveness of this treatment are made. They noted that this study conducted gene therapy at the prenatal stage of brain development, and patients would have to receive this therapy when their brain development is further along. For future studies, the team plans to study how gene therapy effects the mutation in more developed brains.

“For these children and their loved ones, any improvements in motor-cognitive function and quality of life would be worth the try,” Muotri said.