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

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 be infeasible 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 "dont 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 three mouse models of RP and preserved visual function. Cone rescue with CD47 required signal regulatory protein alpha (SIRP) but not microglia or thrombospondin-1 (TSP1), suggesting that CD47 interacts with SIRP on non-microglial cells to alleviate degeneration. These findings establish augmentation of CD47-SIRP signaling as a potential treatment strategy for RP and possibly other forms of neurodegeneration.