Author(s): Kapsa RM, Wong SH, Bertoncello I, Quigley AF, Williams B,
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Abstract Targeted correction of mutations in muscle can be delivered by direct i.m. injection of corrective DNA to the dystrophic muscle or by autologous injection of cells that have been genetically corrected after isolation from the individual with the dystrophic muscle. The successful application of chimeraplasty and short fragment homologous replacement to correct the exon 23 nonsense mdx transition at the mouse dys locus has opened up the possibility that with further development, targeted gene correction may have some future application for the treatment of muscular dystrophies. In vitro, application of targeted gene correction at the mdx dys locus results in better correction efficiencies than when applied directly to dystrophic muscle. This suggests that at least for the time being, a strategy involving ex vivo correction may be advantageous over a direct approach for delivery of gene correction to dystrophic muscle. This, particularly in view of recent developments indicating that bone-marrow-derived cells are able to systemically remodel dystrophic muscle, whilst penetration of DNA introduced to muscle is limited to individually injected muscles. Application of targeted gene correction to Duchenne dystrophy needs to account for the fact that about 65\% of Duchenne muscular dystrophy cases involve large frame-shift deletion of gene sequence at the dys locus. Traditionally, whilst targeted gene correction is able to restore point mutations entirely, it remains to be seen as to whether a strategy for the 'correction' of frame shift deletions may be engineered successfully. This communication discusses the possibility of applying targeted gene correction to dystrophic muscle in Duchenne dystrophy.
This article was published in Neuromuscul Disord
and referenced in Journal of Stem Cell Research & Therapy