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Published on: December 22, 2014
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 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.
Insights
Augmenting CD47/SIRPα signaling protected cone photoreceptors from degeneration in retinitis pigmentosa (RP) mouse models. This approach offers a potential new treatment strategy for RP and other neurodegenerative diseases.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Inherited retinal diseases (IRDs), like retinitis pigmentosa (RP), stem from numerous mutations, with gene replacement offering limited success.
- Current treatments for RP are not scalable and may not be suitable for all patients, necessitating alternative therapeutic strategies.
- Microglial phagocytosis increases during cone degeneration in RP, suggesting a role for "don't-eat-me" signals in cone protection.
Purpose of the Study:
- To investigate the potential of CD47, a "don't-eat-me" signal, as a therapeutic target for cone degeneration in retinitis pigmentosa (RP).
- To evaluate the efficacy of cone-specific CD47 expression in protecting photoreceptors and preserving visual function in RP mouse models.
- To elucidate the interaction partners and cellular mechanisms underlying CD47-mediated cone protection.
Main Methods:
- Adeno-associated viral (AAV) vectors were used to deliver CD47 to cone photoreceptors in three distinct mouse models of RP.
- Cone survival, visual function, and the role of CD47-interacting proteins (SIRPα and TSP1) were assessed.
- The necessity of microglia for CD47's prosurvival effects was investigated.
Main Results:
- Cone-specific expression of CD47 significantly promoted cone survival and preserved visual function across all tested RP mouse models.
- The protective effects of CD47 were dependent on its interaction with signal regulatory protein α (SIRPα), but not thrombospondin-1 (TSP1).
- Microglia were found to be dispensable for CD47's prosurvival activity, indicating interaction with non-microglial cells.
Conclusions:
- Augmenting CD47/SIRPα signaling represents a promising therapeutic strategy for retinitis pigmentosa (RP).
- This approach may offer a broader therapeutic benefit for RP patients compared to gene replacement.
- The findings suggest potential applications of CD47/SIRPα modulation in treating other neurodegenerative conditions.
