Editors' ChoiceEYE DISEASE

Inhibiting the executioner may prevent vision loss

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Science Translational Medicine  06 May 2020:
Vol. 12, Issue 542, eabb7094
DOI: 10.1126/scitranslmed.abb7094

Abstract

SARM1 plays a role in photoreceptor survival, and its inhibition presents an alternative way to treat retinal degenerative disease.

Over 30 million people worldwide are affected by various forms of retinal degeneration. Of these, inherited retinal degeneration and age-related macular degeneration are the leading causes of currently untreatable blindness. Photoreceptor cells are specialized neurons found in the back of our eyes that convert light into electrical signals, thus allowing us to see. End-stage retinal degeneration is characterized by the death of photoreceptor cells.

Although we have seen early therapeutic success for gene therapy in treating retinal degeneration, unique challenges still remain. Retinal degeneration is an heterogeneous group of diseases, with more than 260 causative genes, and developing tailored gene therapy for every disease would be extremely difficult; thus, alternative strategies for treating this group of diseases are needed.

Identification of unifying pro-death or pro-survival mechanisms in photoreceptor cells is one such approach, with the potential to offer global therapeutic solutions for the preservation of vision. Sterile alpha and toll/interleukin-1 receptor motif–containing 1 (SARM1) has come to the fore recently in the field of brain research as the “executioner protein” that is highly efficient at triggering neuronal degeneration following injury. However, its role in photoreceptor biology was unknown.

In this study, Ozaki et al. describe a role for SARM1 in prevention of photoreceptor cell death. They demonstrated that SARM1 mediates photoreceptor death through depletion of the essential metabolite NAD (nicotinamide adenine dinucleotide), thus inducing an energy crisis. Genetic deletion of SARM1 promoted photoreceptor cell survival in a rhodopsin knockout (Rho–/–) model, as shown by the preservation of the outer nuclear layer through both histology analysis and optical coherence tomography imaging. SARM1 deficiency maintained the local NAD pool and thereby preserved cone visual function. The latter was confirmed by electroretinography in vivo. However, as the mice retina differs structurally from humans, it remains unclear whether these results are applicable to humans. Nevertheless, this study provides a foundation for future work; SARM1 inhibition by gene therapy might present an alternative global therapeutic approach for prevention of vision loss.

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