High-throughput small molecule screening for developing therapies in nemaline myopathy
Embargo Date
2027-09-25
OA Version
Citation
Abstract
This study presents a comprehensive analysis of high-throughput small molecule screening to develop therapies for Nemaline Myopathy (NM), a debilitating neuromuscular disorder characterized by muscle weakness and the presence of nemaline bodies within muscle fibers. The primary aim was to identify potential therapeutic compounds that could mitigate the pathological features of NM using a klhl41b-/- zebrafish model, an established proxy for human NM pathology. FDA-approved drugs were screened through an innovative drug repurposing approach, revealing several candidate compounds that improved muscle function in the zebrafish model. Key methodologies included breeding and maintaining zebrafish lines, genotyping, and conducting high-throughput screening assays to evaluate drug efficacy based on survival rates, motility improvements, and amelioration of NM phenotypes. Preliminary screening identified 26 potential lead compounds. Of these, 5-Azacytidine was further validated through dose-response assessments, which significantly enhanced motility in the zebrafish model and indicating a viable therapeutic pathway for NM. The implications of these findings extend beyond NM, offering insights into muscle biology, disease pathology, and therapeutic development. This study underscores the utility of the zebrafish model in neuromuscular research and the power of high-throughput screening in uncovering new treatments for rare diseases. The identified compounds offer hope for NM patients, paving the way for further validation and clinical trials to assess their efficacy in humans. This research represents a major step forward in the quest to find effective treatments for NM, demonstrating the potential to improve the quality of life for individuals affected by neuromuscular disorders.
Description
2024