Gene Therapy Reverses Effects of Autism-Linked Mutation in Brain OrganoidsIn a study published May 0

Gene Therapy Reverses Effects of Autism-Linked Mutation in Brain Organoids

In a study published May 02, 2022 in Nature Communications, scientists at University of California San Diego School of Medicine used lab-grown human brain organoids to learn how a genetic mutation associated with autism disrupts neural development. Recovering the function of this single gene using gene therapy tools was effective in rescuing neural structure and function.

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, the research team 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.

Using stem cell technology, the researchers created brain organoids, or “mini-brains,” using cells from Pitt-Hopkins Syndrome patients, and compared their neurodevelopment to controls.

They found that fewer neurons were produced in the TCF4-mutated organoids, and these cells were less excitable than normal. They also often remained clustered together 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.

The team thus tested two different gene therapy strategies for recovering the functional TCF4 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 senior study author Alysson R. Muotri, PhD, professor at UC San Diego School of Medicine.

The team is currently optimizing their recently licensed gene therapy tools in preparation for future clinical trials, in which spinal injections of a genetic vector would hopefully recover TCF4 function in the brain.

— Nicole Mlynaryk