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A new study claims to have given typical function to a gene linked to conditions including autism spectrum disorder (ASD) using gene therapy. The study was conducted on brain organoids, or “mini-brains”, that allowed the researchers to mimic the effects of mutations within the gene and how the change of function improves cognition.
The findings were published in a paper to Nature Communications.
“For these children and their loved ones, any improvements in motor-cognitive function and quality of life would be worth the try,” said senior study author Alysson Muotri in a statement.
The gene in question is called Transcription Factor 4 (TCF4). Integral in the development of the nervous system and brain, mutations within it have been implicated in neuropsychiatric conditions including autism spectrum disorder (ASD) and schizophrenia. However, the exact mechanisms behind why are yet to be uncovered.
Researchers from the University of California San Diego School of Medicine created brain organoids derived from skin cells taken from children with Pitt-Hopkins Syndrome, which causes developmental delays, cognition difficulties, and seizures. The resulting “mini-brains” had a mutation in TCF4, allowing researchers to identify what could occur by using gene therapy to undo the mutation.
The organoids with mutated TCF4 showed multiple developmental differences, including an impaired ability to create new neurons. A mechanism by which TCF4 could be causing this was uncovered, showing that the mutation resulted in lowered expression of a key developmental gene.
"Even without a microscope, you could tell which brain organoid had the mutation”, said Muotri, indicating just how structurally different the organoids were as a result of mutated TCF4.
Compared to the control organoids, the mutated ones had an atypical structure that resulted in disrupted flow between neurons, which likely contributes to the cognitive impairments seen in ASD and similar disorders.
In an attempt to improve the impaired function, the researchers derived two alternative methods of increasing TCF4 levels. Both were successful, and the resulting organoids had improved function, reversing the structural differences brought about by Pitt-Hopkins Syndrome.
“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.
The research is extremely early, and it would need extensive trials to test whether altering TCF4 in a human model would show the same results. It does, however, strongly implicate the gene and illuminate new avenues to improve the quality of life of people with the condition.
