Results highlight the applicability of Maze’s Compass platform to identify and provide insight into pathogenic genetic variants to treat patients in need
SOUTH SAN FRANCISCO, Calif., February 23, 2022–(BUSINESS WIRE)–Maze Therapeutics, a company that translates genetic insights into new precision medicines for patients, today announced the publication in Nature new findings describing a link between genetic variation in UNC13A, a gene essential for nervous system function, and abnormal accumulation of TDP-43, a molecular feature hallmark of amyotrophic lateral sclerosis (ALS) and dementia frontotemporal (FTD). The research was led by Maze Therapeutics co-founder Aaron Gitler, Ph.D., at Stanford University, in collaboration with researchers from Maze Therapeutics and other institutions, including Mayo Clinic, UCSF, the University of Pennsylvania and Johns Hopkins University. The findings help explain how a genetic variant of UNC13A and dysfunctional TDP-43 can lead to the development of ALS or FTD.
“The findings released today fill a long-standing gap in understanding the development of ALS and FTD, two serious neurodegenerative diseases that have no known cures or broadly effective treatments,” said Eric Green, MD, Ph.D., Senior Vice President. , research & translational sciences. “UNC13A and TDP-43 are well-established contributors to ALS, but how they lead to disease has been a mystery. This study provides the first evidence that these genes act through a common mechanism. Our Compass platform is designed to find genetic information such as this, which is a key step in translating it into therapies for patients. This is an exciting step for the field as we continue to explore new approaches targeting TDP-43 pathology.”
Genome-wide association studies have clearly established that unique genetic traits, or variants, of the UNC13A gene are associated with ALS and FTD in humans, but it is unclear how these variants increase the risk of disease. Maze and his collaborators identified a link between the UNC13A gene variants and TDP-43, an RNA-binding protein often seen in the abnormal aggregates of neurons in these patients. In healthy people, TDP-43 is found in the cell nucleus where it is able to perform its normal functions, but in people with ALS or FTD it is often seen outside the nucleus.
One of the functions of TDP-43 is to act as a repressor of cryptic exon inclusion during RNA splicing, meaning it removes superfluous molecular material that can lead to adverse effects. adversely affect normal protein function or completely prevent protein expression. This research shows that with reduced TDP-43 in the nucleus of neuronal cells, its splicing function could not be performed and resulted in inclusion of a cryptic exon in UNC13A mRNA and reduced expression. of the UNC13A protein. Remarkably, some of the major variants associated with the risk of ALS and FTD in humans are located in the same cryptic exon in UNC13A, suggesting a clear link between the loss of TDP-43 and UNC13A. The results were then validated in vitroshowing that removal of TDP-43 from the nucleus causes formation of cryptic exons in UNC13A which, in turn, decreases levels of the UNC13A protein.
“Thanks to this fruitful collaboration with researchers at Maze, we now understand the connection between two known features of ALS and FTD: remove TDP-43 and the cryptic exons of UNC13A appear, and within those cryptic exons is an important driver of neurological disease,” said Dr. Gitler. “There is still work to be done, and these are not the only drivers of these diseases, but with this understanding we can better focus our efforts on how we might shut down or block the cryptic UNC13A exons.”
About Maze Therapeutics
Maze Therapeutics is a clinical-stage biopharmaceutical company that applies advanced data science methods in tandem with a robust suite of research and development capabilities to advance a pipeline of novel precision medicines for patients with genetically defined diseases. Maze developed the Maze CompassMT platform, a proprietary, purpose-built platform that combines human genetic data, functional genomics tools, and data science technology to map novel connections between known genes and their influence on susceptibility, timing of onset, and the rate of disease progression. Using Compass, Maze is building a broad portfolio of wholly owned and partnered programs. Maze is based in South San Francisco. For more information, visit mazetx.com or follow us on LinkedIn and Twitter.
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Jillian Connell, Maze Therapeutics
Katie Engleman, 1AB