Gene mutations in autism can be reversed with gene therapy

The study was conducted on “mini-brains,” which allowed the researchers to mimic the effects of the mutation within the gene and assess how the change might improve cognitive function.

Microscopic images show significant differences in size and structure between brain organoids derived from a patient with Pitt-Hopkins syndrome (right) and a control group (left) / Photo credit: UC San Diego.

A team of researchers have shown that they can reverse an autism gene mutation by using gene therapy to give the gene a typical function, which can lead to improved cognitive function. The results of the study published in an article on nature communicationshow how mutations within a gene called transcription factor 4 (TCF4) are linked to neuropsychiatric disorders, including autism spectrum disorders (ASD) and schizophrenia.

The study was performed on brain organoids, “mini-brains,” which allowed researchers to mimic the effects of mutations within the gene and understand how mutations affect its function. Derived from skin cells from children with Pitt-Hopkins syndrome, a rare genetic disorder that causes developmental delays, cognitive difficulties and seizures, these “mini-brains” had a TCF4 mutation that allowed researchers to identify what caused the use of gene therapy would happen to reverse the mutation.

Reversal of the autism mutation

Organoids with mutant TCF4 displayed several developmental differences, including a reduced ability to generate new neurons. A mechanism by which TCF4 might cause these effects was also discovered, showing that the mutation resulted in reduced expression of a key developmental gene. ” Even without a microscope, it was possible to determine which brain organoid had the mutationSaid the study’s lead author, Alysson Muotri of the University of California San Diego School of Medicine, noting how the organoids differed structurally due to mutated TCF4.

Microscopic images of developmental stages after immunostaining of brain organoids from patients with Pitt-Hopkins syndrome (PTHS) and parental control / Nature Communications

Compared to control organoids, the mutant organoids had an atypical structure that resulted in a disruption in flow between neurons, likely contributing to the cognitive impairments seen in ASD and related disorders.

To improve impaired function, researchers have developed two alternative methods of increasing TCF4 levels. Both were successful, and the resulting organoids improved function by reversing the structural differences caused by Pitt-Hopkins syndrome. ” The fact that we can correct this gene and even restore the entire neural system at a functional level is incredible. – says Muotri – although more studies are needed to verify whether altering TCF4 in a human model produces the same results. However, it strongly interferes with the gene and opens up new avenues to improve the quality of life of people with this disease.“.

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