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Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype.

ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency. A fundamental question in DMD pathogenesis and dystrophin gene therapy is whether muscle health depends on continuous dystrophin expression throughout the life. Published data suggest that transient dystrophin expression in early life might offer permanent protection. To study the consequences of adulthood dystrophin loss, we generated two strains of floxed mini-dystrophin transgenic mice on the dystrophin-null background. Muscle diseases were prevented in skeletal muscle of the YL238 strain and the heart of the SJ13 strain by selective expression of a therapeutic mini-dystrophin gene in skeletal muscle and heart, respectively. The mini-dystrophin gene was removed from the tibialis anterior (TA) muscle of 8-month-old YL238 mice and the heart of 7-month-old SJ13 mice using an adeno-associated virus serotype-9 Cre recombinase vector (AAV.CBA.Cre). At 12 and 15 months after AAV.CBA.Cre injection, mini-dystrophin expression was reduced by ?87% in the TA muscle of YL238 mice and ?64% in the heart of SJ13 mice. Mini-dystrophin reduction caused muscle atrophy, degeneration and force loss in the TA muscle of YL238 mice and significantly compromised left ventricular hemodynamics in SJ13 mice. Our results suggest that persistent dystrophin expression is essential for continuous muscle and heart protection.

SUBMITTER: Wasala NB

PROVIDER: S-EPMC5181634 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype.

Wasala Nalinda B NB Lai Yi Y Shin Jin-Hong JH Zhao Junling J Yue Yongping Y Duan Dongsheng D

Human molecular genetics 20160422 13

Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency. A fundamental question in DMD pathogenesis and dystrophin gene therapy is whether muscle health depends on continuous dystrophin expression throughout the life. Published data suggest that transient dystrophin expression in early life might offer permanent protection. To study the consequences of adulthood dystrophin loss, we generated two strains of floxed mini-dystrophin transgenic mice on the dystrophin-null background. Mus ...[more]

PMID: 27106099

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Project description:Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.

Dataset Information

Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype.

Publications

Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype.

Similar Datasets

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