Hereditary Muscle Disease Unit

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Myofibrillar myopathies are rare inherited degenerative disorders of primarily 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. We identified expression of LDB3 isoforms and its interactor proteins myotilin and filamin C (other myofibrillar myopathy-causing gene products) in the central and peripheral nervous system of mouse and human, thus providing the basis for neurological signs and symptoms in patients with mutations in LDB3, filamin C, and myotilin. Using lab generated Ldb3A165V/+ knock-in mouse model, we identified that LDB3 acts as a multivalent interaction hub and as a signaling adaptor in a major mechanosensor protein assembly, directly binds to filamin C and HSP70, and facilitates recognition of mechanically unfolded filamin C by the Chaperone assisted selective autophagy (CASA) in skeletal muscle. The disease-causing mutation impairs CASA-mediated filamin C disposal leading to myofibrillar myopathy. At present there remains a high unmet need of the development of disease modifying therapies to treat the underlying cause of LDB3-MFMs. During the past year, we focused our efforts in prevention or reversing the disease pathology in Ldb3A165V/+ knock-in mouse model (Manuscript in preparation) To this end, we have completed preclinical trials of allele silencing using AAV9-shRNA-miR-Ldb3 or Scramble-shRNA-miR administered by intramuscular injection in adult knock-in mice. A single intramuscular injection induced knockdown of mutant LDB3 that led to reversal of muscle pathology and improved muscle strength and function in mice at one month and 3 months post-treatment follow up. Mice treated before the onset of muscle pathology did not develop muscle disease during 5 months post-treatment follow up. Moreover, we have identified treatment response biomarkers which will be useful in future clinical trials of patients with LDB3-MFM. Overall, our results demonstrate that the disease mechanism in LDB3-MFM involves dominant gain of function by mutant LDB3 and Knockdown of mutant protein is expected to improve or stabilize muscle function and pathology in patients with MFM.