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Abstract Details

AAV gene therapy for TNNT1-associated Nemaline myopathy
Neuromuscular and Clinical Neurophysiology (EMG)
S32 - Therapeutics of Genetic Neuromuscular Diseases (4:40 PM-4:48 PM)
005

Nemaline myopathy (NM) is a non-dystrophic congenital myopathy. The hallmarks of this disorder are early onset weakness, hypotonia, skeletal deformities and rod-like inclusions within the sarcolemma of muscle cells. Several gene mutations have been identified in NM. Of these, a non-sense mutation in the TNNT1 gene (encoding for the slow skeletal muscle isoform of troponin T) results in a selective atrophy of slow-twitch myofibers and in a fatal form of NM named Amish Nemaline Myopathy (ANM). There is no treatment for ANM, but the development of an AAV gene therapy is viable and explored in our study. Such an approach requires restricting the expression of TNNT1 to slow-twitch myofibers, thus avoiding deleterious effects associated with the presence of this protein in cardiac cells and fast-twitch myofibers. We accomplished high efficiency muscle transduction and myofiber-type specificity using microRNA de-targeting techniques.


Building AAV vectors with type I myofiber specificity in a preclinical study on Nemaline myopathy.
We designed AAV vectors carrying microRNA target cassettes to silence the expression of the desired protein within the heart and fast-twitch myofibers. In the first part of the study we tested AAV vectors carrying GFP (green fluorescent protein) in wild-type mice. In the second part of the study we will be testing the therapeutic efficacy of AAV vectors carrying TNNT1 in Tnnt1-/- mice. In both cases tissues are harvested after the injection (intramuscular or via tail vein) for molecular and histological studies.
In wild-type mice, the intramuscular delivery of AAV vectors carrying cassettes to silence GFP expression in the heart and fast-twitch myofibers, resulted in an overall reduction of the protein in these areas. Work is ongoing to establish the transduction efficiency and safety after systemic delivery of the newly designed vectors.
An efficient and myofiber-specific protein expression can be achieved with newly-designed AAV vectors.
Authors/Disclosures
Eleonora D'Ambrosio, MD (Umass chan medical center)
PRESENTER
Dr. D'Ambrosio has nothing to disclose.
No disclosure on file
No disclosure on file
No disclosure on file
Kevin Strauss Kevin Strauss has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AveXis.
No disclosure on file
No disclosure on file