ADAR mediated RNA editing for treatment of collagen VI related muscular dystrophy
Awardee: Russell Butterfield
Institution: University of Utah
Grant Amount: $70,133.00
Funding Period: February 1, 2024 - January 31, 2025
Summary:
The collagen VI related muscular dystrophies (COL6-RD) are inherited disorders of muscle characterized by progressive weakness and a combination of distal joint laxity and proximal joint contractures. Missense mutations substitute the glycine residues in the conserved Gly-x-y repeat of the triple helical (TH) domain are the most common mutation in COL6-RD patients. This mutation allows incorporation of abnormal chains into secreted tetramers resulting in a dominant negative effect. Currently, there are no treatment for these disorders and the dominant negative mutations pose significant challenges for developing novel treatments since simple gene-replacement will not be effective to counter the dominant-negative mechanism. In this study, we propose to apply an in-situ RNA editing strategy by recruiting adenosine deaminase acting on RNA (ADAR) with guide RNA to simultaneously correct multiple G-to-A dominant negative mutations in COL6-RD patient-derived fibroblasts. We hypothesize this strategy will significantly decrease the mutant alleles’ presence at mRNA level and result in decreased intracellular retention and increased deposition of collagen VI matrix.