Journal ArticleDOI
Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production.
Jay S. Charleston,Frederick J. Schnell,Johannes Dworzak,Cas Donoghue,Sarah Lewis,Lei Chen,G. David Young,Anthony J. Milici,Jon Voss,Uditha DeAlwis,Bruce M. Wentworth,Louise R. Rodino-Klapac,Zarife Sahenk,D. Frank,Jerry R. Mendell +14 more
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TLDR
This study provides Class II evidence of the muscle cell penetration, exon skipping, and induction of novel dystrophin expression by eteplirsen, as confirmed by 4 assays.Abstract:
Objective To describe the quantification of novel dystrophin production in patients with Duchenne muscular dystrophy (DMD) after long-term treatment with eteplirsen. Methods Clinical study 202 was an observational, open-label extension of the randomized, controlled study 201 assessing the safety and efficacy of eteplirsen in patients with DMD with a confirmed mutation in the DMD gene amenable to correction by skipping of exon 51. Patients received once-weekly IV doses of eteplirsen 30 or 50 mg/kg. Upper extremity muscle biopsy samples were collected at combined study week 180, blinded, and assessed for dystrophin-related content by Western blot, Bioquant software measurement of dystrophin-associated immunofluorescence intensity, and percent dystrophin-positive fibers (PDPF). Results were contrasted with matched untreated biopsies from patients with DMD. Reverse transcription PCR followed by Sanger sequencing of newly formed slice junctions was used to confirm the mechanism of action of eteplirsen. Results Reverse transcription PCR analysis and sequencing of the newly formed splice junction confirmed that 100% of treated patients displayed the expected skipped exon 51 sequence. In treated patients vs untreated controls, Western blot analysis of dystrophin content demonstrated an 11.6-fold increase (p = 0.007), and PDPF analysis demonstrated a 7.4-fold increase (p Conclusion Taken together, the 4 assays, each based on unique evaluation mechanisms, provided evidence of eteplirsen muscle cell penetration, exon skipping, and induction of novel dystrophin expression. Classification of evidence This study provides Class II evidence of the muscle cell penetration, exon skipping, and induction of novel dystrophin expression by eteplirsen, as confirmed by 4 assays.read more
Citations
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Noncoding RNA therapeutics - challenges and potential solutions.
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Current Clinical Applications of In Vivo Gene Therapy with AAVs.
Jerry R. Mendell,Jerry R. Mendell,Samiah Al-Zaidy,Louise R. Rodino-Klapac,Kimberly Goodspeed,Steven J. Gray,Christine N. Kay,Sanford L. Boye,Shannon E. Boye,Lindsey A. George,Stephanie Salabarria,Manuela Corti,Barry J. Byrne,Jacques P. Tremblay +13 more
TL;DR: This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity.
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Therapeutic developments for Duchenne muscular dystrophy.
TL;DR: This Review outlines important developments in these research areas and specifically focuses on new therapies that are in the clinical trial phase or have already been approved for Duchenne muscular dystrophy.
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Antisense technology: an overview and prospectus
TL;DR: In this article, the authors describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications.
Journal ArticleDOI
Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy.
D. Frank,F.J. Schnell,Cody Akana,Saleh El-Husayni,Cody A. Desjardins,Jennifer E. Morgan,Jay S. Charleston,Valentina Sardone,Joana Domingos,George Dickson,Volker Straub,Michela Guglieri,Eugenio Mercuri,Laurent Servais,Francesco Muntoni +14 more
TL;DR: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.
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Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management
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