Our long-term goal is to find effective therapeutics for treatment of Nemaline myopathy (NM). NM is the most common form of non-dystrophic congenital myopathy, having an incidence of 1/20,000 in some populations. It is a slow or non-progressive disease, characterized by the presence of Nemaline bodies in the affected muscle tissue, by muscle weakness and by the absence of muscle regeneration. NM is a heterogeneous group of myopathies of variable severity: different types of NM can range from neonatal lethal to mild adult onset. To date, there is no effective treatment for this disease. Mutations in nine different genes have been linked to NM, with six of these encoding skeletal muscle sarcomere thin filament-associated proteins, including Cofilin 2 (CFL2). No relationships exist between gene mutations and disease severity or other phenotypes. Gene expression profiling of a heterogeneous group of NM patients uncovered a consistent signature for NM; how these changes in gene expression contribute to disease onset and/or severity is not clear. We have developed a novel Drosophila model of NM, using mutations in the Drosophila CFL2 ortholog, twinstar (tsr). This model displays the hallmarks of NM: Nemaline bodies, muscle weakness and, in the severe condition, premature death. In our less severe condition, muscle function is reduced without gross alterations to the sarcomere. We will use our novel model to address the critical gaps in both available treatments for this disease and in our understanding of the contributions of NM signature genes to disease development and severity. Taking advantage of the fast generation time, reproducibility and penetrance of the phenotype, the genetic tools available, and the ability to perform cost effective, relatively high throughput screens, we propose two aims: In the first, we will screen an FDA approved drug library to identify drugs that delay or eliminate NM symptoms. These studies depend on our robust model, our recently developed methods for drug application, and our assays streamlined for such a high throughput screen. We expect to find FDA approved drugs that impact the formation or severity of NM. In the second, we will determine how NM signature genes contribute to NM disease severity. We will first assess gene expression profiles in our mild and strong NM conditions. After validation, we will compare this set of genes with patient NM data generated by our collaborator, Dr. Alan Beggs. Conserved genes that are similarly regulated will then be analyzed for their contribution to disease in our fly model. These data will enhance our understanding of NM heterogeneity, provide insights to drug effectiveness and supply targets for future drug development. Together the work outlined in this proposal with shed new light on NM: we will identify a short list of drugs and clinically relevant genes that can be validated, via our collaboration with Dr. Beggs, first in vertebrate and mammalian disease models and, ultimately, in patients.
Patients diagnosed with Nemoline Myopathy have muscle weakness and decreased mobility and, in some cases, suffer from premature death. No cure exists. Our research will identify FDA approved drugs and novel target genes that slow or inhibit progression of this disease.
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