FGF21 via retinal glial modeling preserves photoreceptor function in retinitis pigmentosa

Retinitis pigmentosa comprises >60 rare genetic disorders with retinal degeneration. The trial cost and time to develop >60 different gene therapies are high, so understanding the mechanisms of functional loss in RP may lead to more general treatments. Fibroblast growth factor 21 (FGF21), a neuroprotectant, was given intraperitoneally twice a week from postnatal week 4 to 10, during rod and cone loss, preserved photoreceptor function and the morphology of supporting Muller glial cells. Single-cell transcriptomics of retinal cells, showed that FGF21 receptor Fgfr1 was specifically expressed in Muller glia and astrocytes. FGF21 treatment predominantly affected genes in Muller glia and astrocytes with increased expression of serum response factor, immediate-early genes, as well as axon development and synapse formation pathway genes. FGF21 also decreased retinal pigmented epithelium (RPE) fatty acid metabolism and decreased rod photoreceptor ATP metabolic processes. In summary, FGF21 protects against photoreceptor degeneration in the P23H model of RP. Understanding cellular and metabolic changes in RP may lead to a more general therapeutic approach.