We are honored to support groundbreaking discoveries related to alpha-Dystroglycanopathy, thanks to our supporters.
The alpha-Dystroglycanopathies (aDG) represent a large spectrum of neuromuscular and neurodevelopmental disorders. Infant-onset aDG includes some of the most severe forms of congenital muscular dystrophy. While significantly affecting muscle function since birth, some of the more debilitating aspects of these disorders are brain and eye malformations that impair learning and vision.
There are (at least) 19 genes whose mutations can lead to an aDG making this CMD subtype genetically and clinically heterogeneous and hindering therapy development. Most known aDG -related genes converge on a shared biochemical pathway that controls the glycosylation of the transmembrane glycoprotein, called alpha-dystroglycan.
M. Chiara Manzini, Developing an array of Dystroglycanopathy mutants in zebrafish for convergent high-throughput drug screening. Funding: 2022-2024.
Mouse models have proven only partially suitable for preclinical studies due to early embryonic or perinatal lethality. This has prevented the generation of a full-body mutant mouse that mimics human disease in the brain, eye, and muscle. More recently, through the work of Manzini’s group and others, the zebrafish has emerged as a good model for aDG research.
This project aims to establish an array of zebrafish mutants for aDG glycosylation, to compare disease progression in the brain, eye, and muscle, and test novel therapies in individual mutants and across groups of mutants with similar presentation. Researchers began by generating and characterizing the POMT1 zebrafish model, and they are now preparing to screen a large number of FDA-approved molecules to identify which may have a beneficial impact on the disease. Additionally, the team is developing zebrafish models for three other genes: POMGnT2, POMGnT1 and LARGE1, where candidate compounds can also be tested. The goal of this study is to generate data that may support the development of new therapies for aDG.
Kevin Wright, Synaptic defects in a mouse model of dystroglycanopathy. Funding: 2020-2022.
Cure CMD provided seed-funding for Dr. Wright’s aDG research in 2020-2022, which has led to follow-up funding from the MDA and the NINDS-NIH.
Data generated from work funded by Cure CMD were used to obtain these larger grants. Dr. Wright’s work focuses on the neurological symptoms experienced by many aDG -affected individuals. His team will continue to use a range of genetic models to determine how aDG controls synapse development and function in the brain, and test whether gene therapy approaches can correct synaptic defects and reduce seizure susceptibility. These studies will provide insight into Dystroglycan function in the nervous system and lay the foundation for therapeutic interventions to correct neurological defects in aDG.
Genetic Prevalence Estimate for POMGnT1
Thanks to our grant from the Chan Zuckerberg Initiative’s Rare as One Project, Cure CMD was invited to submit two recessive genes to the Broad Institute’s Rare Genomes Project to calculate estimated global prevalence. Using the Broad Institute’s Genome Aggregation Database (gnomAD), the largest human reference database containing genetic data from more than 140,000 contributors, and genetic data from participants in the Congenital Muscle Disease International Registry, scientists were able to estimate the frequency of aDG cases due to mutations in the POMGnT1 gene. Calculations indicate that there are approximately 10,000 affected individuals worldwide, and an estimated 436 in the United States.
Since performing this calculation, the Broad team has created an open access tool called GeniE, including the results of POMGnT1 frequency calculations now publicly accessible.
Among diverse applications, this prevalence estimate can now be used to attract industry investors. Cure CMD is grateful to CZI for the opportunity, and the Broad Institute for providing this additional tool to advance treatment development for aDG.
Learn more about aDG on Cure CMD’s alpha-dystroglycanopathy information page. You can also check out Cure CMD’s Research Funding Portfolio to learn about other projects we’ve funded, and our research strategy for the CMD’s.