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RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice.

Publication ,  Journal Article
Liu, J; Wallace, LM; Garwick-Coppens, SE; Sloboda, DD; Davis, CS; Hakim, CH; Hauser, MA; Brooks, SV; Mendell, JR; Harper, SQ
Published in: Mol Ther Nucleic Acids
April 29, 2014

Recent progress suggests gene therapy may one day be an option for treating some forms of limb girdle muscular dystrophy (LGMD). Nevertheless, approaches targeting LGMD have so far focused on gene replacement strategies for recessive forms of the disease. In contrast, no attempts have been made to develop molecular therapies for any of the eight dominantly inherited forms of LGMD. Importantly, the emergence of RNA interference (RNAi) therapeutics in the last decade provided new tools to combat dominantly inherited LGMDs with molecular therapy. In this study, we describe the first RNAi-based, preclinical gene therapy approach for silencing a gene associated with dominant LGMD. To do this, we developed adeno-associated viral vectors (AAV6) carrying designed therapeutic microRNAs targeting mutant myotilin (MYOT), which is the underlying cause of LGMD type 1A (LGMD1A). Our best MYOT-targeted microRNA vector (called miMYOT) significantly reduced mutant myotilin mRNA and soluble protein expression in muscles of LGMD1A mice (the TgT57I model) both 3 and 9 months after delivery, demonstrating short- and long-term silencing effects. This MYOT gene silencing subsequently decreased deposition of MYOT-seeded intramuscular protein aggregates, which is the hallmark feature of LGMD1A. Histological improvements were accompanied by significant functional correction, as miMYOT-treated animals showed increased muscle weight and improved specific force in the gastrocnemius, which is one of the most severely affected muscles in TgT57I mice and patients with dominant myotilin mutations. These promising results in a preclinical model of LGMD1A support the further development of RNAi-based molecular therapy as a prospective treatment for LGMD1A. Furthermore, this study sets a foundation that may be refined and adapted to treat other dominant LGMD and related disorders.

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Published In

Mol Ther Nucleic Acids

DOI

ISSN

2162-2531

Publication Date

April 29, 2014

Volume

3

Issue

4

Start / End Page

e160

Location

United States

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology
 

Citation

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Liu, J., Wallace, L. M., Garwick-Coppens, S. E., Sloboda, D. D., Davis, C. S., Hakim, C. H., … Harper, S. Q. (2014). RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice. Mol Ther Nucleic Acids, 3(4), e160. https://doi.org/10.1038/mtna.2014.13
Liu, Jian, Lindsay M. Wallace, Sara E. Garwick-Coppens, Darcée D. Sloboda, Carol S. Davis, Chady H. Hakim, Michael A. Hauser, Susan V. Brooks, Jerry R. Mendell, and Scott Q. Harper. “RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice.Mol Ther Nucleic Acids 3, no. 4 (April 29, 2014): e160. https://doi.org/10.1038/mtna.2014.13.
Liu J, Wallace LM, Garwick-Coppens SE, Sloboda DD, Davis CS, Hakim CH, et al. RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice. Mol Ther Nucleic Acids. 2014 Apr 29;3(4):e160.
Liu, Jian, et al. “RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice.Mol Ther Nucleic Acids, vol. 3, no. 4, Apr. 2014, p. e160. Pubmed, doi:10.1038/mtna.2014.13.
Liu J, Wallace LM, Garwick-Coppens SE, Sloboda DD, Davis CS, Hakim CH, Hauser MA, Brooks SV, Mendell JR, Harper SQ. RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice. Mol Ther Nucleic Acids. 2014 Apr 29;3(4):e160.
Journal cover image

Published In

Mol Ther Nucleic Acids

DOI

ISSN

2162-2531

Publication Date

April 29, 2014

Volume

3

Issue

4

Start / End Page

e160

Location

United States

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology