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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Effective regeneration of dystrophic muscle using autologous iPSC-derived progenitors with CRISPR-Cas9 mediated precise correction.
TL;DR: It is hypothesized that precise genetic editing in IPSC using CRISPR-Cas9 technology, coupled with MPC differentiation and autologous transplantation, can lead to safe and effective muscle repair and may provide an optimal autOLOGous stem cell-based approach to treat the dystrophic pathology and improve the quality of life for patients with DMD.
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Non-covalent binding of nucleic acids with gold nanoparticles provides their stability and effective desorption in environment mimicking biological media.
Anna V. Epanchintseva,Anton S. Dolodoev,Alina E. Grigor’eva,Boris P. Chelobanov,Dmitrii V. Pyshnyi,Elena I. Ryabchikova,Inna A. Pyshnaya +6 more
TL;DR: It is shown that non-covalent binding of siRNAs with a surface of AuNPs provides desorption of both strands, which is necessary for siRNA functioning in living cells, and could be considered as an important way to construct siRNA and ssDNA delivery systems based on AuNPS.
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Accurate Dystrophin Quantification in Mouse Tissue; Identification of New and Evaluation of Existing Methods
Margriet Hulsker,Ingrid E.C. Verhaart,Laura van Vliet,Annemieke Aartsma-Rus,Maaike van Putten +4 more
TL;DR: A Western blot protocol is provided that allows sensitive and accurate dystrophin quantification in preclinical studies and is able to detect dystrophic levels as low as 0.2% in a reproducible manner.
Journal ArticleDOI
The macrophage as a Trojan horse for antisense oligonucleotide delivery.
TL;DR: The issues surrounding ASO-mediated exon skipping efficacy for DMD are discussed, research aimed at improving targeted ASO delivery is outlined, and the use of the inflammatory cell as a Trojan horse is outlined.
Journal ArticleDOI
Saponins as Natural Adjuvant for Antisense Morpholino Oligonucleotides Delivery In Vitro and in mdx Mice
TL;DR: This study investigated a few saponins for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo, and demonstrated that optimization of saponin in molecular size and composition are key factors to achieve enhanced PMO exon-skipping efficiency.
References
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Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management
Katharine Bushby,Richard S. Finkel,David J. Birnkrant,Laura E. Case,Paula R. Clemens,Linda H. Cripe,Ajay Kaul,Kathi Kinnett,Craig M. McDonald,Shree Pandya,James Poysky,Frederic Shapiro,Jean Tomezsko,Carolyn M. Constantin +13 more
TL;DR: These recommendations provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care.
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Craig M. McDonald,Richard T. Abresch,Gregory T. Carter,William M. Fowler,E. R. Johnson,David D. Kilmer,B. J. Sigford +6 more
TL;DR: A tremendous heterogeneity of severity among males with Becker's muscular dystrophy is suggested, with mean intellectual and neuropsychologic function within normal limits, but with a large variability in intelligence quotient scores.
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Dystrophin and mutations: one gene, several proteins, multiple phenotypes
TL;DR: Current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions are focused on.
Journal ArticleDOI
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.
Sebahattin Cirak,Virginia Arechavala-Gomeza,Michela Guglieri,Lucy Feng,Silvia Torelli,Karen Anthony,Stephen Abbs,M. E. Garralda,John P. Bourke,Dominic J. Wells,George Dickson,Matthew J.A. Wood,Steve D. Wilton,Volker Straub,Ryszard Kole,Stephen B. Shrewsbury,Caroline Sewry,Jennifer E. Morgan,Kate Bushby,Francesco Muntoni +19 more
TL;DR: The safety and biochemical efficacy presented show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy.
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.