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Optimization of Internally Deleted Dystrophin Constructs

Lookup NU author(s): Dr Mojgan Reza, Dr Steven Laval, Dr Andreas Roos, Professor Hanns Lochmuller


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Duchenne muscular dystrophy (DMD) is a severe, genetic muscle disease caused by the absence of the sarcolemmal protein dystrophin. Gene replacement therapy is considered a potential strategy for the treatment of DMD, aiming to restore the missing protein. Although the elements of the dystrophin molecule have been identified and studies in transgenic mdx mice have explored the importance of a number of these structural domains, the resulting modified dystrophin protein products that have been developed so far are only partially characterized in relation to their structure and function in vivo. To optimize a dystrophin cDNA construct for therapeutic application we designed and produced four human minidystrophins within the packaging capacity of lentiviral vectors. Two novel minidystrophins retained the centrally located neuronal nitric oxide synthase (nNOS)-anchoring domain in order to achieve sarcolemmal nNOS restoration, which is lost in most internally deleted dystrophin constructs. Functionality of the resulting truncated dystrophin proteins was investigated in muscle of adult dystrophin-deficient mdx mice followed by a battery of detailed immunohistochemical and morphometric tests. This initial assessment aimed to determine the overall suitability of various constructs for cloning into lentiviral vectors for ex vivo gene delivery to stem cells for future preclinical studies.

Publication metadata

Author(s): Reza M, Laval SH, Roos A, Carr S, Lochmuller H

Publication type: Article

Publication status: Published

Journal: Human Gene Therapy Methods

Year: 2016

Volume: 27

Issue: 5

Pages: 174-186

Print publication date: 01/10/2016

Online publication date: 31/07/2016

Acceptance date: 28/07/2016

ISSN (print): 1946-6536

ISSN (electronic): 1946-6544

Publisher: Mary Ann Liebert, Inc.


DOI: 10.1089/hgtb.2016.026


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Funder referenceFunder name
305121European Commission
305444European Commission
98482Medical Research Council (MRC) Centre for Neuromuscular Diseases UK
BM1207Cooperation of Science and Technology (COST) Action
G1002274Medical Research Council (MRC) Centre for Neuromuscular Diseases UK