Potential limitations of microdystrophin gene therapy for Duchenne muscular dystrophy. JCI Insight 2024 May 07;9(11)
Date
05/07/2024Pubmed ID
38713520Pubmed Central ID
PMC11382885DOI
10.1172/jci.insight.165869Scopus ID
2-s2.0-85195630545 (requires institutional sign-in at Scopus site) 1 CitationAbstract
Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (microdystrophins) are underway for Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with 4 microdystrophin constructs (3 in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using AAV doses comparable with those in clinical trials. We achieved high levels of microdystrophin expression in striated muscles with cardiac expression approximately 10-fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease occurred with 2 of the microdystrophins. The detrimental cardiac effect appears to be caused by variable competition (dependent on microdystrophin design and expression level) between microdystrophin and utrophin at the cardiomyocyte membrane. There may also be a contribution from an overloading of protein degradation. The significance of these observations for patients currently being treated with AAV-microdystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, these findings suggest that microdystrophin treatments need to avoid excessively high levels of expression in the heart and that cardiac function should be carefully monitored in these patients.
Author List
Hart CC, Lee YI, Xie J, Gao G, Lin BL, Hammers DW, Sweeney HLAuthor
Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDependovirus
Disease Models, Animal
Dystrophin
Genetic Therapy
Genetic Vectors
Humans
Male
Mice
Mice, Inbred mdx
Muscle, Skeletal
Muscular Dystrophy, Duchenne
Myocytes, Cardiac
Utrophin
