Stargardt macular dystrophy and evolving therapies

ABSTRACT

Introduction: Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments.

Areas covered: Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending.

Expert opinion: Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans.

KEYWORDS:

• C20-D3-vitamin A
• Stargardt macular dystrophy
• visual cycle
• complement inhibition
• stem cell therapy
• ABCA4
• gene therapy
• SAR422459

Article highlights

• Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that may cause central vison loss and currently lacks therapies.

• Investigational oral therapies for STGD1 aim to decrease accumulation of Vitamin A dimers and lipofuscin in the retina and RPE, and include ALK-001, isotretinoin, VM200, emixustat, and A1120. There is suggestion of efficacy in mouse models of STGD1, though evidence of efficacy in humans is currently lacking.

• Visual cycle suppression is associated with nyctalopia, delayed dark-adaptation, and dyschromatopsia.

• Intravitreal avacincaptad pegol is a C5 complement inhibitor under investigation for STGD1.

• Embryonic stem cell derived RPE cell transplantation for STGD1 has shown early safety and tolerability in a small phase I/II clinical trial.Further research will assess potential efficacy with respect to visual function and anatomic improvements. ABCA4 gene therapy with viral vectors and nanoparticles holds promise as a potential treatment for STGD1, though no results of a phase I/II trial are available at this time.

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Declaration of interest

TA Ciulla had an employment relationship with, and equity ownership in, Ophthotech Corporation during manuscript conception and initial preparation. He subsequently had an employment relationship with, and equity ownership in, Spark Therapeutics. This work was undertaken in his role as Volunteer Clinical Professor at Indiana University School of Medicine, and does not reflect any views or opinions of these corporations or management. B Lam serves as a consultant for Spark Therapeutics and receives study funding from Sanofi, StarGen, and Alkeus. A Berrocal serves on advisory boards for Dutch Ophthalmic Research Center (DORC), Allergan, Alcon, Zeiss, Phoenix, and Visunex Medical Systems. 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 relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.