A Renaissance for Antisense Oligonucleotide Drugs in Neurology

Yokota, Toshifumi; Takeda, Shin’ichi; Lu, Qilong; Partridge, Terence A.; Nakamura, Akinori; Hoffman, Eric P.

doi:10.1001/archneurol.2008.540

Cited by 59 publications

(47 citation statements)

References 18 publications

(23 reference statements)

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“…The amount of dystrophin, nNOS and BDG correlated to clinical severity and BMD patients with deletions equivalent to those created by exon 51 skipping have higher dystrophin levels than either those with large multiexon deletions, or those harbouring exon 53 skippable deletions (26). These findings demonstrate the therapeutic potential of the protein that will be generated by exon 51 skipping trials whilst the functionality of other dystrophins, especially those with larger internal deletions, is less clear (43,(95)(96)(97).…”

Section: Functionality Of the De Novo Dystrophin Proteinmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

Arechavala‐Gomeza¹,

Anthony²,

Morgan³

et al. 2012

CGT

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Duchenne muscular dystrophy (DMD) is the most common childhood neuromuscular disorder. It is caused by mutations in the DMD gene that disrupt the open reading frame (ORF) preventing the production of functional dystrophin protein. The loss of dystrophin ultimately leads to the degeneration of muscle fibres, progressive weakness and premature death. Antisense oligonucleotides (AOs) targeted to splicing elements within DMD pre-mRNA can induce the skipping of targeted exons, restoring the ORF and the consequent production of a shorter but functional dystrophin protein. This approach may lead to an effective disease modifying treatment for DMD and progress towards clinical application has been rapid. Less than a decade has passed between the first studies published in 1998 describing the use of AOs to modify the DMD gene in mice and the results of the first intramuscular proof of concept clinical trials. Whilst phase II and III trials are now underway, the heterogeneity of DMD mutations, efficient systemic delivery and targeting of AOs to cardiac muscle remain significant challenges. Here we review the current status of AO-mediated therapy for DMD, discussing the pre-clinical, clinical and regulatory hurdles and their possible solutions to expedite the translation of AO-mediated exon skipping therapy to clinic.

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Section: Functionality Of the De Novo Dystrophin Proteinmentioning

confidence: 99%

Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

Arechavala‐Gomeza¹,

Anthony²,

Morgan³

et al. 2012

CGT

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“…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).…”

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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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141

124

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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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“…These include the drug PTC124, 5 which allows read-through of nonsense mutations, and antisense oligonucleotides (AOs), which induce exon skipping and restore the reading frame in boys with out-of-frame deletions. 6,7 These early trials require selection of sufficiently well-preserved muscles for the evaluation of induced dystrophin production, which is the primary outcome assessed. 8 Recently MRI has been used for quantification of atrophy of the small foot muscles in chronic patients with diabetic neuropathy.…”

mentioning

confidence: 99%

Muscle histology vs MRI in Duchenne muscular dystrophy

Kinali¹,

Arechavala‐Gomeza²,

Çırak³

et al. 2011

Neurology

137

127

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Objective: There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well-preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation. Methods:We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD Ͼ8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0-4 (normal-severe). Results:In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius Ͼ soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p ϭ 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3-4 grades associated with a more severe fibro-adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10-16.6 years. Conclusion:This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials. Neurology ® 2011;76:346-353 GLOSSARY AO ϭ antisense oligonucleotide; DMD ϭ Duchenne muscular dystrophy; EDB ϭ extensor digitorum brevis; KAFO ϭ knee-ankle-foot orthosis; NSA ϭ number of signal averages; TE ϭ echo time; TR ϭ repetition time.The progressive loss of muscle fibers and their replacement by fat and connective tissue is part of the disease course of DMD.1 Despite several exhaustive natural history studies on the clinical course of DMD, the progression of pathology in individual muscle groups is poorly defined. 2Information on muscle pathology in DMD is limited to the muscles that are biopsied at the time of diagnosis (often quadriceps femoris), 2 the mean age at diagnosis being ϳ4.5 years. 3,4 There are now early clinical trials using novel genetic-based techniques in boys with DMD with the aim to restore dystrophin expression. These include the drug PTC124, 5 which allows

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A Renaissance for Antisense Oligonucleotide Drugs in Neurology

Cited by 59 publications

References 18 publications

Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

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

Muscle histology vs MRI in Duchenne muscular dystrophy

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