Researchers at UCLA Health have shown in lab-grown human brain cells that boosting the activity of a healthy gene copy can offset the effects of a mutation linked to autism.
The findings, published in Nature Neuroscience, suggest a new direction for treating autism and related neurodevelopmental conditions, though the work is still at an early stage.
Autism is highly heritable, and roughly 15% of its genetic risk comes from new mutations that appear for the first time in a child rather than being inherited from a parent. Many of these mutations disable one of the two copies of a gene. Because a single working copy often cannot produce enough of the gene’s product on its own, neurodevelopment can be altered. Most current autism treatments address symptoms resulting from these genetic mutations rather than underlying biology.
The UCLA team, led by Dr. Daniel Geschwind, focused on two genes strongly tied to autism, CHD8 and SCN2A. CHD8 helps regulate other genes involved in brain development, while SCN2A is essential for neurons to fire electrical signals.
Rather than replacing or editing the faulty gene, the researchers used a modified form of CRISPR to switch up the activity of the remaining healthy copy. They aimed it at enhancers, stretches of DNA that act like dials controlling when and how strongly a gene is expressed and often in a cell-type specific manner. Targeting these dials, instead of the gene itself, was intended to keep the gene’s activity in step with natural brain development and to avoid overshooting into harmful overexpression of the gene.
“Many autism-linked mutations leave a person with one working copy of a gene instead of two,” said Geschwind, the Gordon and Virginia MacDonald distinguished professor of Human Genetics, Neurology and Psychiatry at UCLA. “Our results show that, in human cell models, it’s possible to turn up that remaining copy and move cells back toward typical development. This is a key first step, and it gives us a new way to think about addressing the biology underlying these conditions.”
The team tested the approach in two kinds of human stem cell-derived models: cultures of excitatory neurons and cortical organoids, which are small clusters of brain-like tissue that mimic aspects of early brain development and key characteristics of neurodevelopmental disorders also seen in affected individuals.
Key findings included:
- In CHD8 models, boosting the healthy copy reduced abnormal organoid overgrowth and helped cells mature, and shifted gene activity closer to typical levels.
- In SCN2A models, the treatment restored much of the neurons’ normal electrical activity, although some finer electrical properties normalized only in certain cell lines.
- The effect appeared only in cells carrying the mutation. Healthy cells showed no increase in gene activity, and neighboring genes were not affected.
- The timing of treatment mattered, suggesting the approach may work best at specific stages of development.
“What stands out to us is that the approach acted only in cell lines carrying the mutation and left healthy cell lines alone,” said the study’s first author George Chen, a former postdoctoral fellow in the Geschwind lab and current assistant professor of neurology at Children’s Hospital of Los Angeles. “That kind of specificity matters for any future therapy. We are still a long way from the clinic, and there is a lot of work ahead on delivery and timing, but these findings provide hope and give us a clear direction.”
The authors emphasize that the work was done entirely in lab models and that the extent of a shift from mutant to normal levels of expression varied between cell lines, so it is a proof of concept rather than a ready-to-use treatment. Delivering the approach safely to the brain requires improved delivery methods and testing whether it can work after the early developmental window has passed. As the strategy depends on a healthy gene copy, this approach is expected to broadly extend to other neurodevelopmental conditions caused by a single faulty copy of a gene.
