Design and Study of Small Molecules That Cleave the RNA That Causes Myotonic Dystrophy Type 1 (DM1)
Abstract
Myotonic dystrophy type 1 (DM1) is a genetic disorder characterized by multisystemic wasting of muscle function, including organ wasting that leads to cardiac disease, respiratory impairment, cataracts, and a host of other significant problems. In particular, DM1 is caused by an RNA repeat expansion [r(CUG)exp where exp denotes an expanded repeat] harbored in the 3 untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. This r(CUG)exp is toxic via a gain of function mechanism; the repeat forms a structure recognized by various RNA binding proteins, in particular muscle blind-like 1 which controls the alternative splicing of various transcripts. Mis-splicing of the muscle-specific chlorideion channel due to MBNL1 sequestration can be directly linked to myotonia. Over more than a decade, the Disney Laboratory has designed small molecules that bind and deactivate r(CUG)exp in patient derived cells and mouse models. Indeed, we have developed nM and pM inhibitors ofr(CUG)exp dysfunction using innovative approaches: onsite drug synthesis in which r(CUG)exp catalyzes the synthesis of its own inhibitor, engendering small molecules with the ability to cross link to its target, and engendering small molecules with the ability to cleave disease causing RNAs directly or by recruiting an endogenous nuclease. Here, bolstered by in vivo studies in which a small molecule cleaves r(CUG)exp selectively, rescues 134 of 138 MBNL1 regulated splicing events, normalizes the transcriptome, and improves myotonia, we propose to develop antisense- or CRISPR- like small molecules into preclinical candidates for the treatment of the root cause of DM1. Importantly, these studies are directly applicable to other microsatellite diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and fragile X associated tremor ataxia syndrome (FXTAS).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1127993
Entities
People
- Brian M Paegel
- Eric T. Wang
- Matthew D Disney
Organizations
- University of Florida