Micro-dystrophin Genes Bring Hope of an Effective Therapy for Duchenne Muscular Dystrophy

Main Text Systemic delivery of genes to muscle using vectors based on recombinant adenovirus-associated virus (rAAV) has been explored extensively in animal models of Duchene muscular dystrophy (DMD) to replace the missing dystrophin gene in both skeletal and cardiac muscles.1,2 A major challenge in...

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Bibliographic Details
Published in:Molecular therapy 2019-03, Vol.27 (3), p.486-488
Main Authors: Davies, Kay E., Guiraud, Simon
Format: Article
Language:English
Subjects:
Actin
Animal models
Becker's muscular dystrophy
Binding sites
Cardiac function
Cardiac muscle
Clinical trials
Cytomegalovirus
Duchenne's muscular dystrophy
Dystrophin
Dystrophin - genetics
Expression vectors
Genes
Genetic Therapy
Genotype & phenotype
Humans
Localization
mRNA
Muscular dystrophy
Muscular Dystrophy, Duchenne - genetics
Mutation
Patients
Phenotypes
Proteins
Recovery of function
Regulatory sequences
Skeletal muscle
Spectrin
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Summary:Main Text Systemic delivery of genes to muscle using vectors based on recombinant adenovirus-associated virus (rAAV) has been explored extensively in animal models of Duchene muscular dystrophy (DMD) to replace the missing dystrophin gene in both skeletal and cardiac muscles.1,2 A major challenge in bringing this approach to the clinic for DMD is the low gene capacity of rAAV (∼5 kb) and the large size of the dystrophin mRNA (14 kb). Loss of either the DAPC or F-actin binding results in DMD, but other in-frame deletions of the gene result in milder forms of the disease, Becker muscular dystrophy (BMD; OMIM: 300376), since the truncated dystrophin molecules are partially functional. Several groups have modified the original BMD patent’s dystrophin mini-gene to obtain a construct that would fit into an rAAV vector together with the appropriate regulatory sequences, but none show full functional recovery.7,8 The efficacy of these mini-genes has improved with the addition of nNOS binding sites by including spectrin repeats 16/179 and codon optimization.10 However, what determines the severity of clinical phenotype is not fully understood.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2019.01.019