Design and Study of Small Molecules That Cleave the RNA That Causes Myotonic Dystrophy Type 1 (DM1)
Abstract
Myotonic muscular dystrophy type 1 (DM1), also known as Steinert’s disease, is the most common adult-onset form of muscular dystrophy, affecting ~1:8000 individuals. Symptoms include muscle weakness and atrophy, difficulty relaxing muscles (myotonia), insulin insensitivity, cataracts, and cardiac arrhythmia. DM1 is caused when three DNA building blocks, or nucleotides, are repeated too many times in a gene, also known as triplet repeat expansion. In DM1, the major cause of toxicity and symptoms occurs when the gene is transcribed into a biomolecule known as RNA. During this transcription process, the triplet repeat expansion, CUG, adopts into a three-dimensional structure that looks like a bobby pin, or a hairpin-like structure. This three-dimensional structure binds and inactivates a protein named Muscleblind-like 1 (MBNL1) that is responsible for regulating other RNAs. The interaction between the DM1 hairpin and MBNL1 is central to the pathology of DM1; when CUG sequesters (binds and activates) MBNL1, other RNAs are not processed correctly by the cell and form defective proteins. Among many others, two RNAs processed incorrectly encode the muscle-specific chloride ion channel and insulin receptor proteins, with direct ties to muscle weakness and insulin insensitivity associated with DM1. DM1, as well as other diseases caused by repeat expansions including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), DM type 2, and fragile X-associated tremor ataxia syndrome (FXTAS) are all Fiscal Year 2018 (FY18) Areas of Encouragement and share common causes of disease pathology. Our studies to de-activate the RNA that causes DM1 are broadly applicable including to ALS, FTD, and FXTAS. Any neurological or neuromuscular disease that affects military personnel affect our military readiness. Indeed, military service is associated with an increased risk to develop both ALS and FTD. Further, myotonia in general and myotonic dystrophy in particular have been diagnosed in military personnel and affect service fitness. Thus, understanding how to short-circuit disease processes with drugs would advance new therapeutic paradigms for these important classes of disorders and will also make our military more prepared to deal with threats. Over more than a decade, the Disney Laboratory has designed drug-like compounds that bind and deactivate CUG in patient-derived cells and mouse models. Indeed, we have developed highly potent inhibitors of CUG-associated toxicity using various innovative approaches. Here, we have proposed a two-pronged approach to develop drugs that remove the toxic RNA that causes DM1 as a therapeutic strategy. In the first approach, we will design drugs that bind the RNA and directly cleave it such that it cannot bind MBNL1. The approach is bolstered by our recent studies in a mouse model of DM1. Our lead drug cleaves the RNA, rescues DM1-associated defects, and improves myotonia. Thus, we will optimize this lead drug to bind tightly and selectively to the DM1 RNA, without binding to other RNAs in a cell, and then cleave the toxic agent directly. We will comprehensively study the optimal compound in a DM1 mouse model, including dosing regimen and reversal of DM1-associated symptoms, to afford a preclinical candidate. We recently developed an innovative approach to use the body’s innate immune system to degrade selectively a disease-causing RNA. That is, the drug only degrades its intended target in disease-affected cells; it has no effect on healthy cells. This approach, which we call RIBOTACs (Ribonuclease targeting chimeras), could revolutionize how repeat expansion diseases are treated. Briefly, we will tether a lead small molecule that selectively targets the DM1 RNA with a building block that activates a cellular protein that functions in the immune system by destroying viruses. Usually, this protein is only activated when a cell encounters a virus. We will activate the pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910718
Entities
People
- Matthew D Disney
Organizations
- Scripps Research
- United States Army