A drug discovery team in Nottingham has identified small molecules that destroy the toxic RNA spots inside the cells of people with myotonic dystrophy type 1 (DM1). This matters because DM1 is the most common adult muscular dystrophy, affecting over 100,000 patients in developed countries. There is currently no treatment. The disease shortens average life expectancy to 58 years, progressively weakening muscles and damaging the heart, brain, and digestive system. In later stages, difficulty swallowing leads to fatal chest infections. The root cause is a genetic mutation that produces faulty RNA, which clumps into spots inside the cell nucleus and disrupts normal function. The researchers are now refining these chemical starting points to make them more selective and suitable for oral administration. If successful, the drug would target most or all features of the disease—not just muscle symptoms, but also the cognitive impairment, heart problems, and excessive daytime sleepiness that patients experience. Because the approach attacks the fundamental molecular defect, it could halt or reverse the disease’s progression across multiple organ systems, transforming a condition that currently has no treatment options.
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Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It is a highly debilitating condition affecting more than 100,000 patients in developed countries with an average life expectancy of 58 years. DM1 is primarily a neuromuscular disorder, which also affects a range of other systems including the heart, brain, endocrine and digestive systems. Patients may also show specific patterns of psychological dysfunction and personality traits, cognitive impairment/mental retardation and excessive daytime sleepiness. All features show an obvious deterioration with time and difficulty swallowing and sucking food into the lungs in the later stages of the disease contribute towards chest infections and represent a major cause of morbidity and mortality. There is no treatment for DM1. DM1 is caused by a repeat expansion mutation in the 3' untranslated region of the DMPK gene. Unaffected people have 5 to 30 copies of this sequence whereas patients may have hundreds or sometimes thousands of copies. When expressed the DMPK expansion transcripts remain in the nucleus where they form distinct spots or foci. Professors Chris Hayes and David Brook at the University of Nottingham developed an assay to screen for compounds that might provide a treatment for DM1. They identified small molecules that target a novel protein and destroy the spots in DM1 cells, thereby leading to a significant reduction in the faulty RNA and other molecular features of the disorder. Their drug discovery approach, in collaboration with Argenta, a Charles River company, is based on targeting this novel protein, by refining the chemical starting points to make them more selective and more suitable for oral administration to patients. The multisystem nature of DM1 provides particular challenges but Professors Hayes and Brook anticipate that a successful drug would target most/all features of the disease
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