Translational development of splice-modifying antisense oligomers

ABSTRACT

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.

KEYWORDS:

• Rare diseases
• exon skipping
• alternative splicing
• Duchenne muscular dystrophy
• spinal muscular atrophy
• antisense oligomer
• dystrophin
• adaptive clinical trial

Article highlights

• Proof of concept studies have provided compelling evidence that antisense nucleic acid analogs can modify gene expression by mediating exon selection during pre-mRNA processing, yielding induced protein isoforms that can modulate disease severity.

• Antisense oligomer-mediated exon selection was first proposed as a strategy to re-frame the dystrophin transcript and moderate consequences of dystrophin mutations that disrupt the open reading frame, and later extended to exon retention as a therapy for spinal muscular atrophy.

• The translation of splice modifying therapies for Duchenne muscular dystrophy and spinal muscular atrophy has been constrained by several issues: the small patient numbers, clinical and genetic heterogeneity, variable disease progression and difficulties in defining clinical and surrogate endpoints. These issues are further compounded when participants are stratified to satisfy trial requirements regarding mutation subtype, age, pathology, clinical history and standards of medical care.

• International cooperation between clinical care professionals, industry, academia, regulatory agencies, and most importantly, patient communities has been critical to the development of new therapies for rare diseases.

This box summarizes key points contained in the article.

Declaration of interest

SD Wilton and S Fletcher are consultants for Sarepta Therapeutics. They have also received research funding from the National Health & Medical Research Council of Australia and the Muscular Dystrophy Association. They also involved with collaborate research projects with Sarepta Therapeutics. MI Bellgard is also supported by the National Health & Medical Research Council of Australia and by the EU’s RD-Connect. Furthermore, L Price has received research support from Muscular Dystrophy Western Australia & the Parry Foundation (Australia). Finally, AP Akkari is a Director at Shiraz Pharmaceuticals Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors are funded by the National Health and Medical Research Council of Australia, the Medical & Health Research Infrastructure Fund Government of Western Australia, Department of Health and the Muscular Dystrophy Association (USA).