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陕西快乐十分记录:Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa
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Retinitis pigmentosa (RP) is a genetically heterogenous disease that lacks effective treatment. In RP, there is degeneration of cone photoreceptors in the eye, often leading to complete blindness. The reasons for cone degeneration remain largely unknown. Development of therapies that preserve cones and vision in patients with RP, particularly in a mutation-independent manner, would benefit from a greater understanding of the underlying pathological mechanisms. We examined immune responses in RP mice during the period of cone degeneration and identified soluble CX3CL1 (sCX3CL1) as a promising therapy for cones. Viral-mediated expression of sCX3CL1 prolonged cone survival in different RP models and improved visual function. These results establish viral delivery of sCX3CL1 as a potential treatment for RP and other retinal disorders.
Retinitis pigmentosa (RP) is a disease that initially presents as night blindness due to genetic deficits in the rod photoreceptors of the retina. Rods then die, causing dysfunction and death of cone photoreceptors, the cell type that mediates high acuity and color vision, ultimately leading to blindness. We investigated immune responses in mouse models of RP and found evidence of microglia activation throughout the period of cone degeneration. Using adeno-associated vectors (AAVs), delivery of genes encoding microglial regulatory signals led to the identification of AAV serotype 8 (AAV8) soluble CX3CL1 (sCX3CL1) as a promising therapy for degenerating cones. Subretinal injection of AAV8-sCX3CL1 significantly prolonged cone survival in three strains of RP mice. Rescue of cones was accompanied by improvements in visual function. AAV8-sCX3CL1 did not affect rod survival, microglia localization, or inflammatory cytokine levels in the retina. Furthermore, although RNA sequencing of microglia demonstrated marked transcriptional changes with AAV8-sCX3CL1, pharmacological depletion of up to ～99% of microglia failed to abrogate the effect of AAV8-sCX3CL1 on cone survival. These findings indicate that AAV8-sCX3CL1 can rescue cones in multiple mouse models of RP via a pathway that does not require normal numbers of microglia. Gene therapy with sCX3CL1 is a promising mutation-independent approach to preserve vision in RP and potentially other forms of retinal degeneration.
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Author contributions: S.K.W. and C.L.C. designed research; S.K.W., Y.X., P.R., and C.M.H. performed research; S.K.W., Y.X., P.R., and C.M.H. analyzed data; and S.K.W. and C.L.C. wrote the paper.
Reviewers: S.H.T., Columbia University; and M.L.V., University of Utah.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901787116/-/DCSupplemental.
Published under the PNAS license.