Augmentation of CD47/SIRPα signaling protects cones in genetic models of retinal degeneration

Sean K Wang,Yunlu Xue,Constance L Cepko

doi:10.1172/jci.insight.150796

Abstract

Inherited retinal diseases, such as retinitis pigmentosa (RP), can be caused by thousands of different mutations, a small number of which have been successfully treated with gene replacement. However, this approach has yet to scale and may not be feasible in many cases, highlighting the need for interventions that could benefit more patients. Here, we found that microglial phagocytosis is upregulated during cone degeneration in RP, suggesting that expression of “don’t-eat-me” signals such as CD47 might confer protection to cones. To test this, we delivered an adeno-associated viral (AAV) vector expressing CD47 on cones, which promoted cone survival in 3 mouse models of RP and preserved visual function. Cone rescue with CD47 required a known interacting protein, signal regulatory protein α (SIRPα), but not an alternative interacting protein, thrombospondin-1 (TSP1). Despite the correlation between increased microglial phagocytosis and cone death, microglia were dispensable for the prosurvival activity of CD47, suggesting that CD47 interacts with SIRPα on nonmicroglial cells to alleviate degeneration. These findings establish augmentation of CD47/SIRPα signaling as a potential treatment strategy for RP and possibly other forms of neurodegeneration.

Highlights

A major obstacle in developing treatments for inherited retinal diseases (IRDs) is the enormous genetic heterogeneity of pathogenic mutations
To assess if microglia during the later stages of retinitis pigmentosa (RP) might phagocytose cones, retinas from these mice were immunostained for cone arrestin, a marker of all cones
To more sensitively measure microglial phagocytic activity, we explanted retinas from rd1;CX3CR1GFP/+ and sighted CX3CR1GFP/+ animals and incubated them with yeast particles conjugated to pHrodo Red, a pH-dependent dye that fluoresces upon lysosomal acidification

Summary

Introduction

A major obstacle in developing treatments for inherited retinal diseases (IRDs) is the enormous genetic heterogeneity of pathogenic mutations. For a minority of IRDs, gene replacement therapy with adeno-associated viral (AAV) vectors has led to promising results in clinical trials and, in one instance, a successful commercial drug [1, 2]. This strategy has yet to reach the vast majority of patients and may not be feasible for those with less common, gain-of-function, or unidentified mutations. Given these challenges, another approach to treating RP and other IRDs would be to develop mutation-agnostic therapies that preserve cone photoreceptors. Regardless of the exact etiology, an intervention capable of protecting cones in RP independent of the initial genetic lesion would potentially be beneficial for many patients

Methods

Results

Conclusion