Restoring Dystrophin Expression in Duchenne Muscular Dystrophy Muscle

Hoffman, Eric P.; Bronson, Abby; Levin, Arthur A.; Takeda, Shin’ichi; Yokota, Toshifumi; Baudy, Andreas R.; Connor, Edward

doi:10.1016/j.ajpath.2011.03.050

Cited by 93 publications

(88 citation statements)

References 68 publications

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“…First, each exon must be targeted by a specific bespoke antisense sequence. This strategy requires the design and testing of many different antisense reagents to treat all of the different mutation patterns, entailing substantial investment in time and money to perform toxicology and safety assessments (10). Second, although in-frame mutations are associated with milder BMD forms in 80% of cases, the function and stability of each resulting truncated dystrophin are still unknown (11).…”

mentioning

confidence: 99%

Bodywide skipping of exons 45–55 in dystrophic mdx52 mice by systemic antisense delivery

Aoki

Yokota

Nagata

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Duchenne muscular dystrophy (DMD), the commonest form of muscular dystrophy, is caused by lack of dystrophin. One of the most promising therapeutic approaches is antisense-mediated elimination of frame-disrupting mutations by exon skipping. However, this approach faces two major hurdles: limited applicability of each individual target exon and uncertain function and stability of each resulting truncated dystrophin. Skipping of exons 45-55 at the mutation hotspot of the DMD gene would address both issues. Theoretically it could rescue more than 60% of patients with deletion mutations. Moreover, spontaneous deletions of this specific region are associated with asymptomatic or exceptionally mild phenotypes. However, such multiple exon skipping of exons 45-55 has proved technically challenging. We have therefore designed antisense oligo (AO) morpholino mixtures to minimize self-or heteroduplex formation. These were tested as conjugates with cell-penetrating moieties (vivo-morpholinos). We have tested the feasibility of skipping exons 45-55 in H2K-mdx52 myotubes and in mdx52 mice, which lack exon 52. Encouragingly, with mixtures of 10 AOs, we demonstrated skipping of all 10 exons in vitro, in H2K-mdx52 myotubes and on intramuscular injection into mdx52 mice. Moreover, in mdx52 mice in vivo, systemic injections of 10 AOs induced extensive dystrophin expression at the subsarcolemma in skeletal muscles throughout the body, producing up to 15% of wild-type dystrophin protein levels, accompanied by improved muscle strength and histopathology without any detectable toxicity. This is a unique successful demonstration of effective rescue by exon 45-55 skipping in a dystrophin-deficient animal model. personalized medicine | nucleic acid therapy | molecular therapy | oligonucleotides | gene therapy D uchenne muscular dystrophy (DMD), the commonest form of muscular dystrophy, is characterized by progressive deterioration of muscle function (1). DMD is caused mainly by frame-shifting deletion or nonsense mutations in the DMD gene, which encodes the protein dystrophin (2). At the milder end of the disease spectrum, Becker muscular dystrophy (BMD) is a form of dystrophin deficiency that presents with a large spectrum of severities, from borderline DMD to almost asymptomatic cases. BMD typically results from in-frame deletions in the DMD gene that allow the expression of limited amounts of an internally truncated but partly functional protein (3).Skipping of exons in DMD muscle so as to restore an in-frame and asymptomatic or very mild Becker-like transcript is among the more promising therapeutic approaches to treatment of DMD (4). To this end, systemic administration of antisense oligonucleotides (AOs) targeting specific exon(s) in the DMD gene has been shown to restore the reading frame and induce body-wide production of partially functional BMD-like dystrophin in mouse and dog models of DMD (5-7). Recently, phase I/II human clinical trials with AOs targeting exon 51 have been completed (8, 9).Although promising, future developm...

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confidence: 99%

Bodywide skipping of exons 45–55 in dystrophic mdx52 mice by systemic antisense delivery

Aoki

Yokota

Nagata

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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142

124

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“…While the leaky muscle membrane of DMD assists in the uptake of AOs into a target cell, FSHD myofibers lack this leakiness (64)(65)(66). Hence, to achieve and maintain therapeutic efficacy, PMOs may need to be administered in large and repeated doses.…”

Section: Phosphorodiamidate Morpholino Oligomer (Pmo)mentioning

confidence: 99%

Targeting mRNA for the treatment of facioscapulohumeral muscular dystrophy

Bao

Maruyama

Yokota

2016

IRDR

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“…11,17 Accordingly, it is widely held that with advancing methods, the use of gene therapy will become safer, more efficient and, as such, increasingly widespread. 11,18,19 Gene doping was first defined by the WADA in 2003 and coincided with the technology's inclusion on the agency's 'Prohibited List' of substances/ methods.…”

Section: Gene Therapy Vs Gene Dopingmentioning

confidence: 99%