Development of Clinical Candidates for the Treatment of Myotonic Dystrophy
Abstract
Background: 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 3D structure that looks like a bobby pin, or a hairpin-like structure. This 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, direct ties to muscle weakness and insulin insensitivity associated with DM1. Alignment with Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Areas and Strategic Goals: DM1, as well as other diseases caused by repeat expansions including frontotemporal dementia (FTD), DM type 2, and fragile X-associated tremor ataxia syndrome (FXTAS) are all FY22 PRMRP Topic Areas and share common causes of disease pathology. Our studies to de-activate the RNA that causes DM1 are broadly applicable including to myotonic dystrophy type 2 (DM2), FTD, and FXTAS. The proposed research directly aligns with the PRMRP Strategic Goal: Develop and evaluate novel treatments, strategies or therapeutic targets, including research to repurpose existing drugs, for associated neurological diseases and psychological conditions. Proposed Studies: Under our previously funded work, we developed an innovative approach to use the body’s immune system to degrade selectively the CUG repeat expansion that causes DM1. Importantly, the drug only degrades its intended target in disease-affected cells and has no effect on healthy cells. This approach, which we call RiboTACs, could revolutionize how repeat expansion diseases are treated. Briefly, our RiboTACs comprise a lead drug that selectively targets the DM1 RNA and 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 recruit this protein to seek out and destroy only the toxic DM1 RNA with a drug-like small molecule, causing its selective degradation. By selectively degrading the RNA, we can alleviate multiple modes of DM1 toxicity. Our proposed research is focused on developing these lead RiboTACs into clinical candidates for the treatment of DM1, accomplished by three aims: (i) optimize lead, drug-like compounds for inhibiting DM1 disease pathology; (ii) comprehensively evaluate the compounds in patient-derived muscle cells and study cellular selectivity across all human RNAs; and (iii) evaluate lead molecules in mouse models by measuring pharmacokinetics and tissue exposure, safety profiles, and therapeutic efficacy. Collectively, our studies will afford clinic candidates for treatment of DM1 by eliminating the disease-causing agent and broadly demonstrate that DM1 and other diseases caused by RNA are viable small molecule drug targets. Ultimate Applicability and Impact: Short-Term Impact: The therapeutic modality of choice for RNA targets has long been antisense oligonucleotides (ASOs). Unfortunately, ASOs suffer from therapeutic liabilities including poor cellular and tissue permeability, and clinical trials of ASOs have been halted due to dose-limiti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310336
Entities
People
- Matthew D Disney
Organizations
- United States Army
- University of Florida