Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of Duchenne muscular dystrophy

Gushchina, Liubov V.; Vetter, Tatyana A.; Frair, E.; Bradley, A.; Grounds, Kelly M.; Lay, Jacob W.; Huang, Nianyuan; Suhaiba, Aisha; Schnell, Frederick J.; Hanson, Gunnar J.; Simmons, Tabatha R.; Wein, Nicolas; Flanigan, Kevin M.

doi:10.1016/j.omtn.2022.10.025

Cited by 6 publications

(2 citation statements)

References 43 publications

(59 reference statements)

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“…By contrast, the splice-shifting morpholino chemistry that we have used in this study has demonstrated safety in humans, with four drugs already FDA-approved for the treatment of Duchenne muscular dystrophy 43 . Several molecular conjugates have shown promise to facilitate the delivery and potency of multiple ASO chemistries in skeletal muscle tissue 30,[44][45][46][47][48][49][50] . To enhance therapeutic benefit in DM1, drugs directed toward DMPK-CUG exp transcripts could be combined with an adjuvant Clcn1-targeting ASO.…”

Section: Discussionmentioning

confidence: 99%

Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy

Kim

Antoury

et al. 2023

Nat Commun

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In myotonic dystrophy type 1 (DM1), deregulated alternative splicing of the muscle chloride channel Clcn1 causes myotonia, a delayed relaxation of muscles due to repetitive action potentials. The degree of weakness in adult DM1 is associated with increased frequency of oxidative muscle fibers. However, the mechanism for glycolytic-to-oxidative fiber type transition in DM1 and its relationship to myotonia are uncertain. Here we cross two mouse models of DM1 to create a double homozygous model that features progressive functional impairment, severe myotonia, and near absence of type 2B glycolytic fibers. Intramuscular injection of an antisense oligonucleotide for targeted skipping of Clcn1 exon 7a corrects Clcn1 alternative splicing, increases glycolytic 2B levels to ≥ 40% frequency, reduces muscle injury, and improves fiber hypertrophy relative to treatment with a control oligo. Our results demonstrate that fiber type transitions in DM1 result from myotonia and are reversible, and support the development of Clcn1-targeting therapies for DM1.

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Section: Discussionmentioning

confidence: 99%

Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy

Kim

Antoury

et al. 2023

Nat Commun

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show abstract

“…Automated dystrophin quantification was performed using a custom algorithm developed in the General Analysis 3 module of NIS-Elements AR software v5.30 (Nikon), similar to a previously published approach. 44 , 45 For the diaphragm and TA, the analysis was performed on whole tissue sections after manual exclusion of artifacts. For the heart, the analysis was performed on three transversely oriented 0.5 × 0.5 mm regions of interest from each section.…”

Section: Methodsmentioning

confidence: 99%