Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies

ABSTRACT

Introduction

Inherited retinal disorders (IRDs) are the most common cause of certifiable blindness in working-age adults in the UK. There are currently no treatments for the majority of patients, resulting in considerable morbidity with lifelong socioeconomic implications. Twelve percent of all genetic disease variants are nonsense mutations, which encode a premature termination codon (PTC). The resultant transcript is either degraded through nonsense-mediated decay (NMD) or translated into a truncated protein. Nonsense suppression therapy aims to bypass and allow translation beyond the PTC, creating a full-length protein and possible phenotypic rescue. The responsible agents, named translational readthrough-inducing drugs (TRIDs), have been in continuous development to maximize efficiency and minimize toxicity. These include aminoglycosides, aminoglycoside derivatives and non-aminoglycoside small molecule drugs and have been successfully applied to a number of diseases in recent preclinical studies.

Areas covered

This review provides an update in the advancements of nonsense suppression therapy in the treatment of IRDs, including an overview of this process and NMD, advancements in the development of TRIDs and barriers to clinical trials including drug developments, disease modeling, and patient selection.

Expert opinion

Clinical trials are forthcoming for patients with IRDs to determine TRIDs suitability as viable therapy options.

KEYWORDS:

• Aminoglycosides
• genetic eye disease
• inherited retinal disorders
• nonsense-mediated decay
• nonsense mutations
• nonsense suppression
• PTC124
• readthrough
• small molecules
• translation

Article highlights

• Mechanisms of nonsense mutations, nonsense-mediated decay (NMD), and nonsense suppression therapy.

• Updates in development of translational readthrough-inducing drugs (TRIDs) and NMD inhibitors.

• Recent applications to models of inherited retinal dystrophies.

• Improvements in drug delivery and clinical trial considerations.

Acknowledgments

Thanks to the Wellcome Trust (grant 205174/Z/16/Z), National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, Fight for Sight UK and Moorfields Eye Charity.

Declaration of interest

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by the Wellcome Trust (grant 205174/Z/16/Z), National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, Fight for Sight UK and Moorfields Eye Charity.