scispace - formally typeset
Open AccessJournal Article

Eteplirsen for the Treatment of Duchenne Muscular Dystrophy (DMD) (S42.001)

Reads0
Chats0
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

Citations
More filters
Journal ArticleDOI

In Silico Screening Based on Predictive Algorithms as a Design Tool for Exon Skipping Oligonucleotides in Duchenne Muscular Dystrophy

TL;DR: An in silico pre-screening approach is proposed, based on predictive statistical modelling, to predict exon skipping efficacy at each position of a target exon in Duchenne muscular dystrophy.
Journal ArticleDOI

Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy.

TL;DR: This study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and describes discrete clusters of disease progression for the first time, as measured by the North Star Ambulatory Assessment (NSAA) total score.
Journal ArticleDOI

Angubindin-1 opens the blood-brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system.

TL;DR: This proof‐of‐concept study demonstrated that intravenously injected angubindin‐1 increased the permeability of the blood–brain barrier and enabled transient delivery of subsequently administered antisense oligonucleotides into the mouse brain and spinal cord, leading to silencing of a target RNA without any overt adverse effects.
Journal ArticleDOI

Peptide-conjugate antisense based splice-correction for Duchenne muscular dystrophy and other neuromuscular diseases

TL;DR: When tested in animal models, PPMOs demonstrate effective exon skipping in target muscles and prolonged duration of dystrophin restoration after a treatment regime, highlighting the obstacles that must be overcome prior to translating the animal-based research into clinical trials tailored to the needs of patients suffering from neuromuscular diseases.
Journal ArticleDOI

Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping.

TL;DR: The potential of therapeutic alternative splicing is discussed, with a particular focus on targeted exon skipping using Duchenne MD as an example, and new applications for other inherited rare diseases where redundant or dispensable exons may be amenable to exon-skipping ASO intervention as precision medicine are speculated.
References
More filters
Journal ArticleDOI

Profiles of neuromuscular diseases. Duchenne muscular dystrophy.

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.
Journal ArticleDOI

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

Local Dystrophin Restoration with Antisense Oligonucleotide PRO051

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.
Related Papers (5)