The Effect of Autism-Linked Mutation in Brain Organoids has been revealed in gene therapy

The Effect of Autism-Linked Mutation in Brain Organoids has been revealed in gene therapy ...

Scientists at the University of California San Diego School of Medicine used human brain organoids to show how a genetic mutation associated with a profound form of autism disrupts neural development.

To recover genes function effectively, using gene therapy techniques, rescued neural structure and function.

Mutations in Transcription Factor 4 (TCF4), an essential protein in brain development, have been linked to several neurological and neuropsychiatric disorders. Although, no one has yet known about it. What happens to the human brain whenTCF4is mutated.

Researchers focused on Pitt-Hopkins Syndrome, an ASD specifically caused by mutations inTCF4. Children with this genetic condition have profound cognitive and motor difficulties and are usually non-verbal.

Existing mouse models of Pitt-Hopkins Syndrome fail to accurately mimic patients neural characteristics, therefore the UC San Diego team instead created a human research model of the disorder. Using stem cell technology, patients skin cells were transformed into stem cells, which were then transformed into three-dimensional brain organoids.

The brain organoids were identified in the initial observations, which included a slew of structural and functional differences between theTCF4-mutated samples and their controls.

Alysson R. Muotri, a senior research author, has been diagnosed with the mutation in the brain. She is the director of the UC San Diego Stem Cell Program, and a member of the Sanford Consortium for Regenerative Medicine.

TheTCF4-mutated organoids were significantly smaller than normal organoids, and many of them were not actually neurons, but neural progenitors. These simple cells are meant to multiply and then mature into special brain cells, but in the mutated organoids, some part of this process had gone awry.

TheTCF4mutation has led to downstream dysregulation ofSOXgenes and the Wnt pathway, two important molecular signals that lead embryonic cells to multiply, mature into neurons, and migrate to the correct location in the brain.

Due to this dysregulation, neural progenitors did not multiply effectively and thus less cortical neurons were formed. The cells that matured into neurons were less excitable than normal and often remained clustered together instead of putting themselves into finely-tuned neural circuits.

This unusual cellular structure altered the flow of neural activity in the mutated brain organoid, which, according to authors, would likely to alter cognitive and motor function down the line.

We were surprised to see such significant developmental issues at all of these different levels, and it left us wondering what we could do to help deal them. Fabio Papes, PhD, an associate professor at the University of Campinas, and a visiting scholar at the University of San Diego School of Medicine, contacted him to write an email. Papes has a great interest in TTC4.

The team used two methods to recover the functional gene in brain tissue. Both methods boostedTCF4 levels, and in doing so, corrected Pitt-Hopkins Syndrome phenotypes at molecular, cellular, and electrophysiological levels.

The fact that we can correct this one gene and the whole neural system, even at a functional level, is amazing, according to Muotri.

Muotri says that these genetic interventions took place at a prenatal stage of brain development, while children would receive their diagnosis and treatment a few years later. Thus, clinical trials must first verify whether a later intervention is still safe and effective. In preparation for such a trial, spinal injections of the genetic vector would hopefully restore TCF4 function in the brain.

Muotri said that any enhancements in motor-cognitive function and quality of life would be beneficial for these children and their children.

"What is truly outstanding about this work is that these researchers are going beyond the lab and working hard to make these findings clear to the clinic," says Audrey Davidow, president of the Pitt Hopkins Research Foundation. This paper is so much more than a stellar academic paper, and it''s a remarkable measure of what well-practiced science can accomplish to hopefully improve human lives.

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