Fibroblast growth factor 21 protects against retinal degeneration in P23H mice

Abstract

Purpose : Retinitis pigmentosa (RP) is a general term for retinal degenerations affecting about 1 in 4000 people in the U.S. It is typically diagnosed in adolescence. Most people with RP are legally blind by age 40. Cellular metabolic gene expression changes indicating starvation coincide with the onset of cone death, suggesting that cones suffer from a metabolic shortage after loss of factors such as rod-derived cone viability factor, which promotes glucose uptake in cones. We investigated if fibroblast growth factor 21 (FGF21), a strong metabolic modulator, protects against retinal degeneration in RP.

Methods : The P23H mutation of rhodopsin (amino acid substitution of histidine for phenylalanine at position 23) is the most common cause (15-18% of all adRP cases in US). In a mouse model of heterozygous P23H mutant mice, long-acting FGF21 PF-05231023 10mg/kg (half-life in mouse serum is 28 hours) or vehicle were intraperitoneally injected twice a week when cone responses start to decrease. After 1-to-2-months of treatment, we examined retinal rod and cone function with electroretinography (ERG, n=22-30), retinal thickness with optical coherence tomography (OCT, n=8-10), and retinal structure with immunohistochemistry (IHC, n=4-5). Rod, cone, Müller cell and other cell responses to FGF21 administration was investigated with single-cell transcriptomic analysis (control: 18,000 cells; FGF21: 12,000 cells). The pathways were investigated using Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO) analysis. The results were validated with immunohistochemistry. Both male and female mice were used. t test, or ANOVA was used for statistical analysis.

Results : In P23H mutant mice, FGF21 protected against photoreceptor degeneration. Retinal function was examined at postnatal week (PW) 4, 7, and 10. FGF21 protected against rod loss at PW7 (a wave amplitude: P<0.001; b wave amplitude: P<0.05) and cone degeneration at PW10 (b wave amplitude: P<0.001; b wave sensitivity: P<0.05) in P23H mutant mice. FGF21 did not change retinal thickness. FGF21 activates serum response factor (P<0.001, FDR<0.001) and neurogenesis potential (P<0.001) in Müller cells. Mild impacts of FGF21 on rod or cone metabolism were observed.

Conclusions : FGF21 protects against photoreceptor degeneration possibly through modulating Müller glial cell neurogenesis potential in retinal degeneration.

This is a 2020 ARVO Annual Meeting abstract.