Hereditary Muscle Disease Unit

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Myofibrillar myopathies are rare inherited degenerative disorders of skeletal and cardiac muscle characterized by primary dissolution of myofibrils near the Z-disc and accumulation of degraded proteins in the sarcoplasm of muscle fibers. The dominant p.Ala165Val mutation in LIM domain binding protein has been reported in several unrelated families with European ancestry. During the past year, we completed characterization of a novel disease mechanism in a knock-in mouse model, identified a new role of LDB3 protein, and published these results. We showed that LDB3 acts as a multivalent interaction hub and as a signaling adaptor in a major mechanosensory assembly, directly binds to filamin C and HSP70, and facilitates recognition of mechanically unfolded filamin C by the CASA autophagy machinery. The disease-causing mutation impairs CASA-mediated filamin C disposal leading to myofibrillar myopathy. At present there are no treatment options available for patients. Allele-specificity and efficacy of siRNA oligos to downregulate the mutant Ldb3 transcript were demonstrated in transfected cell culture systems to inform in vivo approach in mutant mice. We validated shRNA viral vectors for in vivo knockdown of mutant Ldb3 allele in mouse muscle. We started a preclinical trial of allele silencing using these vectors in two separate cohort of mice with goals to prevent the pathology (injections before pathology begins) and reversing the pathology (injections after the onset of disease). GFP expression was visualized throughout the muscle, suggesting efficient viral transduction. Early results confirmed knockdown of mutant allele at RNA and protein level in shRNA-Ldb3 injected muscle compared to control. Studies are ongoing to validate these findings in a larger cohort and to examine extended effects of a single intramuscular injection such as after 3 months on muscle pathology. We anticipate that these preclinical studies will ultimately translate to patients in future clinical trials. There is a growing interest from patient community to develop therapeutics for this disabling neurogenic disease. Patient studies: We enrolled a total of 4 participants in the clinical protocol titled Assessing Clinical Endpoints and Biomarkers in Myotonic Dystrophy Type 1 and Type 2 (ASCEND-DM) (2019-N-0065). The data analysis of 113 patients participated across 6 sites (24 patients at NIH CC) for all 3 study visits in the myotonic dystrophy (DM) clinical research network study (DMCRN; 2014-N-132) was finalized. (Manuscript at submission stage). We developed novel handgrip relaxometer devices to measure hand grip myotonia and conducted a pilot study to characterize and validate the devices in 20 DM1 patients and 10 healthy participants (2014-N-0132). Data analysis is complete (manuscript in submission). We published exome analysis of 66 patients with rare undiagnosed neurodegenerative neuromuscular diseases seen in the Neurogenetics Clinic (2000-N-0043) and identified novel mutations, atypical phenotypes and very rare but potentially treatable hereditary neurodegenerative diseases.