New pharmacotherapies for genetic neuromuscular disorders: opportunities and challenges

ABSTRACT

Introduction: Genetic neuromuscular diseases (NMDs) constitute a heterogeneous group of rare conditions, including some of the most disabling conditions in childhood. Recently, advanced technologies have greatly expanded preclinical and clinical research, and specific therapies have been developed.

Area covered: We provide an overview of novel pharmacological approaches to the main NMDs, including Duchenne muscular dystrophy (DMD), spina muscular atrophy (SMA), X-linked myotubular myopathy, Pompe disease (PD), and myotonic dystrophy type 1, with attention to both achievements and unresolved therapeutic challenges. We conducted a selected review of relevant publications in the last five years identified through PubMed and Scopus. Additional information was derived from the website of clinicaltrials.gov and from the authors’ direct knowledge of research activities.

Expert Opinion: For the first time, targeted therapies have received conditional regulatory approval and have been introduced into clinical care: enzyme replacement therapy for PD, gene expression modulation for DMD and SMA, and gene therapy for SMA. Though not curative, these treatments can improve functioning and increase survival. Issues still to be addressed include: early recognition, definition of new emerging phenotypes, development of more sensitive outcome measures, long-term risk-benefit estimates, high costs sustainability, and criteria for therapy initiation and discontinuation.

KEYWORDS:

• Neuromuscular diseases
• molecular therapies
• genetic therapies
• gene therapy
• spinal muscular atrophy
• Duchenne muscular dystrophy
• Pompe disease
• X-linked myotubular myopathy
• myotonic dystrophy type 1

Article Highlights

• Innovative pharmacological therapies for neuromuscular diseases have been registered for clinical use in the last few years.

• Enzyme replacement therapy for PD, nusinersen and onasemnogene abeparvovec-xioi for SMA, ataluren, and eteplirsen for DMD have been proven effective in significantly improving the clinical course and quality of life of patients and their families.

• Many promising clinical trials are ongoing (e.g., adenovirus-mediated gene-therapies, antisense oligonucleotides mediated strategies, and small molecules therapies), and other strategies are under development (e.g., genome editing, myoblast cell therapy).

• Important issues remain to be addressed, and in particular: early recognition and selection of eligible patients, identification of new emerging phenotypes, risk-benefit estimates, identification of sensitive outcome measures, sustainability of the high cost of new treatments, and definition of valid criteria for therapy initiation and discontinuation.

Declaration of interest

Federica Ricci: travel grants from Biogen, PTC Therapeutics, Sanofi-Genzyme, and Sarepta.

Martina Vacchetti: travel grants from Biogen, Sanofi-Genzyme.

Chiara Brusa: travel grants from Biogen, PTC Therapeutics, and Sanofi-Genzyme.

Liliana Vercelli: travel grants from Sanofi-Genzyme.

Benedetto Vitiello: travel support and consulting fees from Medicine and consulting fees Shire Pharmaceuticals.

Tiziana Mongini: travel grants from Biogen, PTC Therapeutics, Sanofi-Genzyme, and Sarepta. 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.

Reviewer disclosures

A reviewer on this paper discloses that they are a named inventor on exon skipping drugs for Duchenne MD. As such they are entitled to milestone and royalty payments. They have stated that this has not influenced their comments on the manuscript. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author Contribution Statement

Federica Ricci: review concept; acquisition, analysis and interpretation of data and information; drafting of the manuscript.

Martina Vacchetti: acquisition, analysis, and interpretation of data and information; drafting of the manuscript.

Chiara Brusa: acquisition, analysis, and interpretation of data and information; drafting of the manuscript.

Liliana Vercelli: acquisition, analysis, and interpretation of data and information; revision of manuscript.

Chiara Davico: acquisition, analysis, and interpretation of data and information; revision of manuscript.

Benedetto Vitiello: review concept; drafting of the manuscript; critical revision of manuscript for intellectual content.

Tiziana Mongini: review concept; drafting of the manuscript; critical revision of manuscript for intellectual content.

Additional information

Funding

This paper was not funded.