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

Roberts, Paul; Gaffney, Eamonn A.; Whiteley, Jonathan; Luthert, Philip J; Foss, Alexander J.E.; Byrne, Helen M.

doi:10.1167/iovs.17-23177

Cited by 12 publications

(24 citation statements)

References 68 publications

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“…This is because, following the loss of rods and consequent drop in RdCVF concentrations, the loss of cones decreases trophic factor demand until RdCVF levels are healthy once more. This is in contrast to the oxygen toxicity mechanism, considered by the author in previous publications (see Roberts et al, 2017, 2018), which is self-reinforcing; toxically high oxygen levels causing photoreceptor degeneration, leading to a further rise in oxygen levels, and so on.…”

Section: Discussioncontrasting

confidence: 63%

“…11). This does not replicate any of the spatio-temporal patterns of visual field loss (and hence retinal degeneration) observed by Grover et al (1998) (see also Roberts et al, 2018), suggesting that other mechanisms are necessary, either in place of or together with trophic factor starvation-induced degeneration, to explain in vivo disease progression. In Case (iii) mutation-induced rod degeneration was shown to precipitation the formation of cone degenerate patches at the locations of narrow rod degenerate patches, where they would not have otherwise formed, and to drive the expansion of cone degenerate patches (Fig.…”

Section: Discussionmentioning

confidence: 89%

“…We previously developed the first and only models to consider the oxygen toxicity hypothesis (Roberts et al, 2017, 2018). These models are formulated as systems of PDEs in one- and two-dimensions and were the first models of RP to take the key step of accounting for the photoreceptor distribution.…”

Section: Introductionmentioning

confidence: 99%

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Mathematical Models of Retinitis Pigmentosa: The Trophic Factor Hypothesis

Roberts

2021

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Retinitis pigmentosa (RP) is the term used to denote a group of inherited retinal-degenerative conditions that cause progressive sight loss. Individuals with this condition lose their light-sensitive photoreceptor cells, known as rods and cones, over a period of years to decades; degeneration starting in the retinal periphery, and spreading peripherally and centrally over time. RP is a rod-cone dystrophy, meaning that rod health and function are affected earlier and more severely than that of cones. Rods degenerate due to an underlying mutation, whereas the reasons for cone degeneration are unknown. A number of mechanisms have been proposed to explain secondary cone loss and the spatio-temporal patterns of retinal degeneration in RP. One of the most promising is the trophic factor hypothesis, which suggests that rods produce a factor necessary for cone survival, such that, when rods degenerate, cone degeneration follows. In this paper we formulate and analyse mathematical models of RP under the trophic factor hypothesis. These models are constructed as systems of reaction diffusion partial differential equations in one spatial dimension, and are solved and analysed using a combination of numerical and analytical methods. We predict the conditions under which cones will degenerate following the loss of a patch of rods from the retina, the critical trophic factor treatment rate required to prevent cone degeneration following rod loss and the spatio-temporal patterns of cone loss that would result if the trophic factor mechanism alone were responsible for retinal degeneration.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 89%

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Mathematical Models of Retinitis Pigmentosa: The Trophic Factor Hypothesis

Roberts

2021

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“…Characteristic patterns of retinal degeneration in human RP (reproduced, with permission and modifications, from Roberts et al, 2018). Degeneration patterns can be classified into three cases and six subcases (classification system described in Grover et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Inverse Problem Reveals Conditions for Characteristic Retinal Degeneration Patterns in Retinitis Pigmentosa under the Trophic Factor Hypothesis

Roberts

2021

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Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy with a prevalence of about 1 in 4000, affecting approximately 1.5 million people worldwide. Patients with RP experience progressive visual field loss as the retina degenerates, destroying light-sensitive photoreceptor cells (rods and cones), with rods affected earlier and more severely than cones. Spatio-temporal patterns of retinal degeneration in human RP have been well characterised; however, the mechanism(s) giving rise to these patterns have not been conclusively determined. One such mechanism, which has received a wealth of experimental support, is described by the trophic factor hypothesis. This hypothesis suggests that rods produce a trophic factor necessary for cone survival; the loss of rods depletes this factor, leading to cone degeneration. In this paper we formulate a partial differential equation mathematical model of RP in one spatial dimension, spanning the region between the retinal centre (fovea) and the retinal edge (ora serrata). Using this model we derive and solve an inverse problem, revealing for the first time experimentally testable conditions under which the trophic factor mechanism will qualitatively recapitulate the spatio-temporal patterns or retinal regeneration observed in human RP.

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“…It plays a major role in the pathophysiology of various ocular diseases, such as agerelated cataract, macular degeneration, glaucoma, diabetic retinopathy, and retinitis pigmentosa, by affecting cellular and vascular physiological aspects. 1,2 Antioxidants, such as enzymatic antioxidants, vitamins, minerals, carotenoids, and flavonoids, are the primary scavengers of ROS reducing levels of oxidative stress. 3 Cholecalciferol (vitamin-D3 (VIT-D)) has diverse functions, including modulation of inflammation, angiogenesis, oxidative stress, and fibrosis.…”

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confidence: 99%

Vitamin-D3 (α-1, 25(OH) 2D3) Protects Retinal Pigment Epithelium From Hyperoxic Insults

Murugeswari

Firoz

Subramani

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Citation: Murugeswari P, Firoz A, Murali S, et al. Vitamin-D3 (α-1, 25(OH) 2D3) protects retinal pigment epithelium from hyperoxic insults. Invest Ophthalmol Vis Sci. 2020;61(2):4. https://doi.org/10.1167/iovs.61.2.4 PURPOSE.Oxidative stress affects the retinal pigment epithelium (RPE) leading to development of vascular eye diseases. Cholecalciferol (VIT-D) is a known modulator of oxidative stress and angiogenesis. This in vitro study was carried out to evaluate the protective role of VIT-D on RPE cells incubated under hyperoxic conditions. METHODS.Cadaver primary RPE (PRPE) cells were cultured in hyperoxia (40% O 2 ) with or without VIT-D (α-1, 25(OH) 2D3). The functional and physiological effects of PRPE cells with VIT-D treatment were analyzed using molecular and biochemical tools. RESULTS.Vascular signaling modulators, such as vascular endothelial growth factor (VEGF) and Notch, were reduced in hyperoxic conditions but significantly upregulated in the presence of VIT-D. Additionally, PRPE conditioned medium with VIT-D induced the tubulogenesis in primary human umbilical vein endothelial cells (HUVEC) cells. VIT-D supplementation restored phagocytosis and transmembrane potential in PRPE cells cultured under hyperoxia. CONCLUSIONS. VIT-D protects RPE cells and promotes angiogenesis under hyperoxic insult.These findings may give impetus to the potential of VIT-D as a therapeutic agent in hyperoxia induced retinal vascular diseases.Keywords: retinal pigment epithelium, vitamin D, hyperoxia, vascular endothelial growth factor (VEGF), tubulogenesis O xidative stress is the result of an imbalance between the synthesis of reactive oxygen species (ROS) and the levels of antioxidants in the cells. It plays a major role in the pathophysiology of various ocular diseases, such as agerelated cataract, macular degeneration, glaucoma, diabetic retinopathy, and retinitis pigmentosa, by affecting cellular and vascular physiological aspects. 1,2 Antioxidants, such as enzymatic antioxidants, vitamins, minerals, carotenoids, and flavonoids, are the primary scavengers of ROS reducing levels of oxidative stress. 3 Cholecalciferol (vitamin-D3 (VIT-D)) has diverse functions, including modulation of inflammation, angiogenesis, oxidative stress, and fibrosis. 4,5 Recent studies have demonstrated an association between VIT-D and retinal pathophysiological conditions, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity (ROP). 6−8 These studies implicated deficiency of VIT-D to higher risk for early/late AMD, whereas a supplementation leads to delay or prevention in the progression of AMD. 6,9 Although VIT-D receptors as well as enzymes for VIT-D metabolism are present in the retina, choroid, and retinal pigment epithelium (RPE) cells, their functions are still not well understood. 6 VIT-D has been studied as a potential inhibitor of angiogenesis in a mouse model of oxygen-induced ischemic retinopathy (OIR). 10 A correlation of VIT-D and vascular endothelial growth factor (VEGF) has been ob...

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

Cited by 12 publications

References 68 publications

Mathematical Models of Retinitis Pigmentosa: The Trophic Factor Hypothesis

Mathematical Models of Retinitis Pigmentosa: The Trophic Factor Hypothesis

Inverse Problem Reveals Conditions for Characteristic Retinal Degeneration Patterns in Retinitis Pigmentosa under the Trophic Factor Hypothesis

Vitamin-D3 (α-1, 25(OH) 2D3) Protects Retinal Pigment Epithelium From Hyperoxic Insults

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