In a study published May 02, 2022 inNature Communications, scientists at the University of California San Diego School of Medicine investigated how a genetic mutation associated with a profound form of autism stors neural development.
The ability to recover genes function effectively helped restore neural structure and function by using gene therapy techniques.
Mutations in Transcription Factor 4 (TCF4), an essential protein in brain development, have been linked to several neurological and neuropsychiatric disorders, including autism spectrum disorders (ASD) and schizophrenia. However, others are unaware that their presence or absence may have a domino effect on the human brain.
Researchers investigated Pitt-Hopkins Syndrome, an ASD that was specifically caused by mutations inTCF4. Children with this genetic condition have profound cognitive and motor difficulties and are generally non-verbal.
The UC San Diego team used stem cell technology to transform patients skin cells into stem cells, which was then transformed into three-dimensional brain organoids.
The brain organoids were identified in initial observations, indicating a slew of structural and functional differences between theTCF4-mutated samples and their controls.
Alysson R. Muotri, a senior study author, is the author of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine.
Many of the cells were not actually neurons, but neural progenitors. These simple cells are intended to multiply and then mature into special brain cells, but in the mutant organoids, some part of this process had gone unintention.
Two key molecular signals that guide embryonic cells to multiply, mature into neurons, and migrate to the correct location in the brain have been revealed in a series of experiments.
Due to this dysregulation, neural progenitors did not multiply effectively and thus fewer cortical neurons were formed. The cells that matured into neurons were less excitable than normal and often remained clustered together instead of forming themselves into finely-tuned neural circuits.
This atypical cellular structure impeded the flow of neural activity in the mutated brain organoid, which, according to authors, would likely contribute to decreased cognition and motor function down the line.
We were surprised to see such major developmental challenges at all these different levels, and it left us wondering what we might do to help address them. Fabio Papes, PhD, an associate professor at the University of Campinas, and a visiting researcher at the University of San Diego School of Medicine, authored the first novel, Theodore MacDonald, which co-supervised the work with Muotri. Papes has a parent with Pitt-Hopkins Syndrome, which motivated him to studyTCF
Two different gene therapy therapies were tested for the recovery of functional gene in brain tissue. Both methods enhancedTCF4 levels, and in doing so, corrected Pitt-Hopkins Syndrome phenotypes at molecular, cellular, and electrophysiological levels.
According to Muotri, the fact that we can correct this one gene and the whole neural system, even at a functional level, is amazing.
Muotri says that these genetic injections took place at a prenatal stage of brain development, whereas children would receive their diagnosis and treatment a few years later. Therefore, clinical trials must first confirm whether a later intervention is still safe and effective. The team is currently developing their recently licensed gene therapy tools in preparation for such a trial, in which spinal injections of the genetic vector might hopefully help restore TCF4 function in the brain.
Muotri claims that improvements in motor-cognitive function and quality of life would be worthwhile for these children and their families.
"What we do with this research is that these researchers are going beyond the lab and making these findings clinically accessible; that''s a true measure of what well-practiced science can do to hopefully change human lives for the better."