Open AccessJournal Article
Eteplirsen for the Treatment of Duchenne Muscular Dystrophy (DMD) (S42.001)
Jay S. Charleston,F.J. Schnell,Johannes Dworzak,Cas Donoghue,J Lynch,Sarah Lewis,Lei Chen,Louise R. Rodino-Klapac,Zarife Sahenk,Jon Voss,U. DeAlwis,D. Frank,H Eliopoulos,J. Mendell +13 more
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TLDR
The present study used a double‐blind placebo‐controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6‐minute walk test.Abstract:
Objective: Phosphorodiamidate morpholino oligomers (PMOs) are synthetic nucleic acid analogs that can be designed to sequence-specifically block spliceosomes from binding to dystrophin pre-mRNA, resulting in omission of the targeted exon from the transcript and restoration of the reading frame with the goal of enabling synthesis of internally-shortened dystrophin. Background: DMD, a rare, X-linked genetic disease results in progressive muscle degeneration and premature death. DMD is primarily caused by whole exon deletions in the dystrophin gene resulting in a shift of the mRNA reading frame that prevents production of functional dystrophin protein. Design/Methods: As of June 3, 2016, 81 of 150 treated patients had received weekly eteplirsen for ≥1 year. Results: PMO eteplirsen received accelerated approval in the US for patients with a dystrophin gene mutation amenable to exon 51 skipping based on an increase in dystrophin in skeletal muscle in some patients. Mean dystrophin increases as measured by Western blot were observed following 180 weeks of treatment in the pivotal Phase II Studies 201/202 when compared to untreated DMD controls (N=11; +0.85%, p=0.007) and at Week 48 in Phase III Study PROMOVI when compared to baseline (N=12; +0.28%, p=0.008). Immunohistochemistry analysis at Week 180 in Study 201/202 also showed mean increases in dystrophin as measured by % dystrophin-positive fibers (N=11; +16.27%, p 4.5 years of treatment. Conclusions: Eteplirsen is the first exon skipping therapy approved for the treatment of Duchenne muscular dystrophy amenable to exon 51 skipping. Lessons learned from the eteplirsen clinical development program can aid in development of PMO therapies targeting additional exons. Study Supported by: Sarepta Therapeutics, Inc. Disclosure: Dr. Charleston has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Schnell has received personal compensation for activities with Sarepta Therapeutics as a full time employee. Dr. Dworzak has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Donoghue has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Lynch has received personal compensation for activities with Sarepta Therapeutics, Inc. as an employee. Dr. Lewis has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Rodino-Klapac has nothing to disclose. Dr. Sahenk has nothing to disclose. Dr. Voss has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. DeAlwis has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Frank has received personal compensation for activities with Sarepta Therapeutics, Inc. as an employee. Dr. Eliopoulos has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Mendell has received personal compensation for activities with Sarepta Therapeutics, Inc.read more
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Journal ArticleDOI
A comprehensive database of Duchenne and Becker muscular dystrophy patients (0–18 years old) in East China
Xihua Li,Lei Zhao,Shui-zhen Zhou,Chaoping Hu,Yiyun Shi,Wei Shi,Hui Li,Fang Liu,Bingbing Wu,Yi Wang +9 more
TL;DR: The database is the first linking accurate genetic diagnosis with clinical manifestation and treatment status of dystrophinopathy patients in East China and provides comprehensive information essential for further patient management, especially for promotion of international cooperation in developing experimental therapies such as exon skipping and read-through of nonsense mutations targeting a subgroup of DMD patient population.
Journal ArticleDOI
Elusive sources of variability of dystrophin rescue by exon skipping
Maria Candida Vila,Maria Candida Vila,Margaret Benny Klimek,James S. Novak,Sree Rayavarapu,Kitipong Uaesoontrachoon,Jessica F. Boehler,Jessica F. Boehler,Alyson A. Fiorillo,Marshall W. Hogarth,Aiping Zhang,Conner Shaughnessy,Heather Gordish-Dressman,Heather Gordish-Dressman,Umar Burki,Volker Straub,Qi Long Lu,Terence A. Partridge,Terence A. Partridge,Kristy J. Brown,Kristy J. Brown,Yetrib Hathout,Yetrib Hathout,John van den Anker,Eric P. Hoffman,Eric P. Hoffman,Kanneboyina Nagaraju,Kanneboyina Nagaraju +27 more
TL;DR: This study highlights the challenges associated with quantifying dystrophin in clinical trials where a single small muscle biopsy is taken from a DMD patient and suggests that other yet-undefined factors may underlie the observed variability in the success of exon skipping.
Book ChapterDOI
Designing Effective Antisense Oligonucleotides for Exon Skipping.
TL;DR: The design of effective AONs for exon skipping is discussed, allowing the production of truncated but partly functional dystrophin proteins, and slow down the progression of the disease.
Journal ArticleDOI
Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles
Cécile Peccate,Amédée Mollard,Maëva Le Hir,Laura Julien,Graham McClorey,Susan Jarmin,Anita Le Heron,George Dickson,Sofia Benkhelifa-Ziyyat,Matthew J.A. Wood,Thomas Voit,Thomas Voit,Stéphanie Lorain +12 more
TL;DR: Avoiding vector genome loss after AAV injection by PPMO pre-treatment would allow efficient long-term restoration of dystrophin and the use of lower and thus safer vector doses for Duchenne patients.
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The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?
Rangariroyashe H. Chipika,We Fong Siah,Mary Clare McKenna,Stacey Li Hi Shing,Orla Hardiman,Peter Bede +5 more
TL;DR: A systematic review of existing presymptomatic studies in ALS is performed to identify common themes, stereotyped shortcomings, and key learning points for future studies.
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Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.
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Journal ArticleDOI
Local Dystrophin Restoration with Antisense Oligonucleotide PRO051
Judith C.T. van Deutekom,Anneke A.M. Janson,Ieke B. Ginjaar,Wendy S. Frankhuizen,Annemieke Aartsma-Rus,Mattie Bremmer-Bout,Johan T. den Dunnen,Klaas Koop,Anneke J. van der Kooi,Nathalie Goemans,Sjef J. de Kimpe,Peter F. Ekhart,Edna H. Venneker,Gerard Johannes Platenburg,Jan J.G.M. Verschuuren,Gert-Jan B. van Ommen +15 more
TL;DR: Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible.