Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model

Abstract

Retinitis Pigmentosa (RP) is a family of inherited retinal degenerative diseases that leads to blindness. In many cases the disease-causing allele encodes for a gene exclusively expressed in the night active rod photoreceptors. However, because rod death always leads to cone death affected individuals eventually lose their sight. Many theories have been proposed to explain the secondary loss of cones in RP; however, most fail to fully explain the different pathological transition stages seen in humans. Incorporating experimental data of rod and cone death kinetics from two mouse models of RP, we use a mathematical model to investigate the interplay and role of energy consumption and uptake of the photoreceptors as well as nutrient availability supplied through the retinal pigment epithelium (RPE) throughout the progression of RP. Our data driven mathematical model predicts that the system requires a total reduction of approximately 27% to 31% in nutrients available to result in the complete demise of all cones. Simulations utilizing retinal degeneration 1 (rd1) mouse cell count data in which cone death was delayed by altering cell metabolism in cones show that preventing a 1-2% decrease in nutrients available can permanently halt cone death even when 90% have already died. Our results also indicate that the ratio of energy consumption to uptake of cones, Dc, is mainly disrupted during the death wave of the rods with negligible changes thereafter and that the subsequent nutrient decrease is mainly responsible for the demise of the cones. The change in this ratio Dc highlights the compensation that the cones must undergo during rod death to meet the high metabolic demands of the entire photoreceptor population. Global sensitivity analysis confirms the results and suggests areas of focus for halting RP, even at later stages of the disease, through feasible therapeutic interventions.

Knockout of zebrafish interleukin 7 receptor (IL7R) by the CRISPR/Cas9 system delays retinal neurodevelopment

“…Retinitis pigmentosa (RP), the most common inherited and degenerative retinal disease, causes severe vision impairment 38 , 39 . Usually, rods first undergo progressive degeneration, followed by deterioration of cones and retinal pigment epithelium 40 . There is no treatment or cure for RP.…”

Predictive Mathematical Models for the Spread and Treatment of Hyperoxia-induced Photoreceptor Degeneration in Retinitis Pigmentosa

“…4,[40][41][42][43][44] Both treatments have been shown to reduce retinal degeneration in RP. 35,38,39,43,[45][46][47] Several mathematical models have been developed to describe the rod trophic factor, [48][49][50][51][52][53][54] mTOR, 54 and toxic substance [55][56][57] hypotheses (see Roberts et al 58 for a detailed review of the current state-of-the-art in retinal modeling, including models of RP). In an earlier study we developed a one-dimensional (1D) model (fovea to ora serrata) to describe retinal degeneration under the oxygen toxicity hypothesis.…”

Spatio-temporal characterization of S- and M/L-cone degeneration in the Rd1 mouse model of retinitis pigmentosa

“…As in the human disease, loss of rods is followed by a gradual, progressive loss of cones. The underlying pathogenesis of cone degeneration, both in the Rd1 strain and in RP, remains unclear, although a number of mechanisms have been implicated, including depletion of rodderived cone viability factor, oxidative stress, microglial activation, and energetic failure [4][5][6][7].…”