Scientists at the University of California San Diego School of Medicine used human brain organoids to explain how a genetic mutation associated with a profound form of autism disrupts neural development.
To recover the genes function effectively, the neural structure and function were saved thanks to gene therapy techniques.
Mutations in Transcription Factor 4 (TCF4), an essential protein in brain development, have elicited several neurological and neuropsychiatric illnesses, including autism spectrum disorders (ASD) and schizophrenia. However, none of the facts about this fact has been revealed about what happens to the human brain whenTCF4 is mutated.
Researchers studied Pitt-Hopkins Syndrome, an ASD, which is specifically caused by mutations inTCF4. Children with this genetic condition have profound cognitive and motor difficulties and are typically non-verbal.
The UC San Diego team then created a human research model of the condition using stem cell technology. Patients skin cells were then transformed into three-dimensional brain organoids, or mini-brains.
The brain organoids are examined in depth for structural and functional differences between theTCF4-mutated samples and their controls.
Alysson R. Muotri, a senior research author at the University of California in medicine, is the director 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 meant to multiply and then mature into special brain cells, although some part of this process had gone awry.
TheTCF4mutation has resulted in downstream dysregulation ofSOXgenes and the Wnt pathway, two key molecular signals that guide embryonic cells to multiply, mature into neurons, and migrate to the correct location in the brain.
Due to this dysregulation, neural progenitors performed poorly and therefore fewer cortical neurons were produced. The cells that matured into neurons were less excitable than normal and often remained clustered together instead of posing themselves into finely-tuned neural circuits.
The mutated brain organoid''s atypical cellular structure has disrupted neural activity, which according to the authors, would likely lead to impaired cognality and motor function down the line.
We were surprised to see such significant developmental challenges at all of these different levels, and it left us wondering what we could do to do them, according to the first author Fabio Papes, PhD, an associate professor at the University of Campinas and a visiting scholar at the University of San Diego School of Medicine who provided the work. Papes has a friend with Pitt-Hopkins Syndrome, which motivated him to studyTCF4.
The team conducted experiments on two different gene therapy techniques in order to recover the functional gene in brain tissue. Both methods effectively increasedTCF4 levels, and in doing so, corrected Pitt-Hopkins Syndrome phenotypes at molecular, cellular, and electrophysiological scales.
The fact that we can correct this one gene and the whole neural system, even at a functional level, is stunning, according to Muotri.
These genetic therapies took place during a prenatal stage of brain development, whereas children would receive their diagnosis and treatment a few years later. In this context, clinical trials must first establish whether a later intervention is still safe and effective. In this way, the team is developing their recently licensed gene therapy tools to help with the discovery of TCF4 in the brain.
Muotri said that any improvement in motor-cognitive function and quality of life would be a valuable task for these children and their relatives.
"What I feel apart from this work is that these researchers are going beyond the lab and working hard to make these findings clinically acceptable, according to Audrey Davidow, the president of the Pitt Hopkins Research Foundation. This is so much more than a stellar academic paper, and it''s a true measure of what well-practiced science can accomplish to hopefully change human lives for the better."