Search

Antisense oligonucleotide (ASO)-mediated exon skipping can restore the open reading frame of dystrophin transcripts for Duchenne muscular dystrophy (DMD) patients. This allows production of internally deleted dystrophin proteins as found in the later onset, less severely progressive Becker muscular dystrophy. At present, ASOs that induce exon skipping and dystrophin restoration are approved for the treatment of DMD by the regulatory agencies of the United States and Japan. However, approval was based on restoration of very small amounts of dystrophin and the approved ASOs apply to only a subset of patients. This expert perspective evaluates ways to improve ASO efficiency that are currently in or close to clinical trials, as well as ways to improve applicability of this mutation-specific approach. [ABSTRACT FROM AUTHOR]

On December 12, 2019, the Food and Drug Administration (FDA) granted accelerated approval to Sarepta Therapeutics for golodirsen to treat Duchenne muscular dystrophy (DMD) patients with eligible mutations (www.drugs.com/newdrugs/fda-approves-vyondys-53-golodirsen-duchenne-muscular-dystrophy-dmd-patients-amenable-skipping-exon-5119.html). However, most mutations cluster in a hotspot region and as such the skipping of certain exons applies to larger groups of patients, for example, exon 51 skipping would apply to 14% of patients, whereas exon 45 and exon 53 skipping would apply to an additional 9% and 8% of DMD patients [[1]]. Unfortunately, however, Wave recently announced suvodirsen treatment did not result in an increase in dystrophin expression in biopsies from DMD patients treated for 12 or 22 weeks. [Extracted from the article]

Eteplirsen was approved for the treatment of eligible patients with Duchenne muscular dystrophy (DMD) in September 2016 in one of the most, if not the most, controversial approvals ever made by the Food and Drug Administration of the United States. Two years later, the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency gave a negative opinion for eteplirsen treatment. They had done so as well in May 2018, after which Sarepta (the company developing eteplirsen) appealed and a new evaluation was initiated, including a Scientific Advisory Group (SAG) meeting involving DMD experts and patient representatives. However, after reevaluation the opinion of the CHMP remained negative. In this commentary, we outline how differences in the perspective of FDA and EMA can lead to a DMD therapy being approved by FDA but not EMA, and vice versa. [ABSTRACT FROM AUTHOR]

This underlines the fact that the oligonucleotide therapy field has matured, as is also confirmed by the five oligonucleotide drug approvals in the United States (eteplirsen, nusinersen, inotersen, patisiran) and Europe (nusinersen, inotersen, patisiran, and volanesorsen) for the past 4 years, with additional approvals anticipated shortly. Finally, the growing robustness and versatility of oligonucleotide technology were demonstrated as our closing session on clinical updates included oligonucleotide clinical trials in both very large and very small patient populations. The records pushed into the small numbers too, as multiple examples were presented of using oligonucleotide therapies for individual patients. The disease should affect a tissue for which delivery of oligonucleotide therapy has been established in the clinic (central nervous system, eye, and liver). [Extracted from the article]

Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD. A unique aspect of the exon-skipping approach for DMD is that, depending on the size and location of the mutation, different exons need to be skipped. This challenge raises a number of questions regarding the development and regulatory approval of those individual compounds. In this study, we present a perspective on those questions, following a European stakeholder meeting involving academics, regulators, and representatives from industry and patient organizations, and in the light of the most recent scientific and regulatory experience. [ABSTRACT FROM AUTHOR]

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: 'Networking towards clinical application of antisense-mediated exon skipping for rare diseases.' The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting. [ABSTRACT FROM AUTHOR]

An introduction to research articles about exon skipping published within the issue is presented, including an article on antisense-mediated splicing modulation for Duchenne muscular dystrophy, articles on opportunities for more productive crosstalk between scientists and clinician researchers and grants offered by the Cooperation for Science and Technology (COST).