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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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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Guiraud, Simon
description 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.
doi_str_mv 10.1016/j.ymthe.2019.01.019
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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.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2019.01.019</identifier><identifier>PMID: 30765324</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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 &amp; phenotype ; Humans ; Localization ; mRNA ; Muscular dystrophy ; Muscular Dystrophy, Duchenne - genetics ; Mutation ; Patients ; Phenotypes ; Proteins ; Recovery of function ; Regulatory sequences ; Skeletal muscle ; Spectrin</subject><ispartof>Molecular therapy, 2019-03, Vol.27 (3), p.486-488</ispartof><rights>2019 The American Society of Gene and Cell Therapy</rights><rights>2019. 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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. 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phenotype</topic><topic>Humans</topic><topic>Localization</topic><topic>mRNA</topic><topic>Muscular dystrophy</topic><topic>Muscular Dystrophy, Duchenne - genetics</topic><topic>Mutation</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Proteins</topic><topic>Recovery of function</topic><topic>Regulatory sequences</topic><topic>Skeletal muscle</topic><topic>Spectrin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Davies, Kay E.</creatorcontrib><creatorcontrib>Guiraud, Simon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Davies, Kay E.</au><au>Guiraud, Simon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Micro-dystrophin Genes Bring Hope of an Effective Therapy for Duchenne Muscular Dystrophy</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2019-03-06</date><risdate>2019</risdate><volume>27</volume><issue>3</issue><spage>486</spage><epage>488</epage><pages>486-488</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-3</notes><notes>content type line 23</notes><notes>ObjectType-Commentary-1</notes><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30765324</pmid><doi>10.1016/j.ymthe.2019.01.019</doi><tpages>3</tpages><oa>free_for_read</oa></addata></record>
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source ScienceDirect Journals; PubMed Central
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
title Micro-dystrophin Genes Bring Hope of an Effective Therapy for Duchenne Muscular Dystrophy
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