A review of the mechanisms of cone degeneration in retinitis pigmentosa

Narayan, Daniel S.; Wood, J. K.; Chidlow, Glyn; Casson, Robert J.

doi:10.1111/aos.13141

Cited by 153 publications

(142 citation statements)

References 93 publications

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“…In RP, degeneration and, subsequently, death of diseased, mutant rods leads to the non-cell autonomous loss of wild-type cones (2,10,11). However, it is not known if degenerating rods have non-cell autonomous effects on the rods surrounding them.…”

Section: Discussionmentioning

confidence: 99%

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Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Koch

Duong

Hsu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fig. 3. Restoration of PDE6b expression rescues rods and partially restores OS length, in a dose-dependent fashion, and prevents cone death. Pde6b STOP / Pde6b H620Q , Pde6g::CreERT2 mice were injected with 25, 50, or 100 μg/g BW tamoxifen to rescue 30% (T30), 50% (T50), or 70% (T70) of rods, respectively; untreated mutants (mut) and wild-type mice (Pde6b + /Pde6b H620Q , Pde6g::CreERT2, WT) were not injected. Tamoxifen injections were in 1-mo-old mice; at 9 mo of age, retinas were sectioned and immunolabeled. (A) Antibodies: rhodopsin or PDE6b (rod OSs, red) and arrestin (cones, green). Hoechst dye, nuclei, blue. Arrows, arrestin-immunopositive cone cell bodies; arrowheads, arrestin-immunopositive cone OSs. (B) Rhodopsin and arrestin immunolabeled sections were quantitatively analyzed for ONL thickness, cone number, rod OS length and cone IS + OS length. Gray dots, individual mice (n = 4 for each group); horizontal black lines, group means. Treated and untreated groups were compared by a linear regression model: ***P < 0.001. IS, inner segment; ONL, outer nuclear layer; OS, outer segment. (Scale bar, 15 μm.)

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Section: Discussionmentioning

confidence: 99%

“…Most often, RP results from mutations in rod-specific genes, which trigger the cell-autonomous loss of rods that, in turn, causes the non-cell autonomous loss of cones (2). Gene therapy strategies are being intensively developed and tested for RP and other inherited retinal degenerative diseases.…”

mentioning

confidence: 99%

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Koch

Duong

Hsu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…103 The pathways that lead to cone degeneration are diverse and incompletely understood. 28,104 In photoreceptor degenerating conditions, it is often the case that rods are lost before cones; thus, understanding whether cone loss occurs as a result of rod loss or because of the same process that kills rods is key to providing the theoretical basis for preserving cones and, thus, central vision. Cones consume large amounts of energy and impose a higher metabolic cost than rods.…”

Section: Discussionmentioning

confidence: 99%

Glucose metabolism in mammalian photoreceptor inner and outer segments

Narayan

Chidlow

Wood

et al. 2017

Clinical Exper Ophthalmology

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Photoreceptors are the first-order neurons of the visual pathway, converting light into electrical signals. Rods and cones are the two main types of photoreceptors in the mammalian retina. Rods are specialized for sensitivity at the expense of resolution and are responsible for vision in dimly lit conditions. Cones are responsible for high acuity central vision and colour vision. Many human retinal diseases are characterized by a progressive loss of photoreceptors. Photoreceptors consist of four primary regions: outer segments, inner segments, cell bodies and synaptic terminals. Photoreceptors consume large amounts of energy, and therefore, energy metabolism may be a critical juncture that links photoreceptor function and survival. Cones require more energy than rods, and cone degeneration is the main cause of clinically significant vision loss in retinal diseases. Photoreceptor segments are capable of utilizing various energy substrates, including glucose, to meet their large energy demands. The pathways by which photoreceptor segments meet their energy demands remain incompletely understood. Improvements in the understanding of glucose metabolism in photoreceptor segments may provide insight into the reasons why photoreceptors degenerate due to energy failure. This may, in turn, assist in developing bio-energetic therapies aimed at protecting photoreceptors.

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“…Autosomal recessive inheritance accounts for a majority of RP cases (50–60%), with autosomal dominance (30–40%) and X-linked (5–15%) as lesser contributing modes of inheritance (Bunker et al, 1984; Grondahl, 1987; Narayan et al, 2016; Novak-Laus et al, 2002). Approximately 45 loci have been identified, which accounts for only about half of all patients (Hartong et al, 2006; Narayan et al, 2016). Mutations causing RP can be found in genes encoding proteins for a variety of cellular processes, including rod phototransduction (e.g.…”

Section: Retinal Degenerative Diseases (Rdds)mentioning

confidence: 99%

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

Jones

Lü

Girman

et al. 2017

Progress in Retinal and Eye Research

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Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments.

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A review of the mechanisms of cone degeneration in retinitis pigmentosa

Cited by 153 publications

References 93 publications

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa

Glucose metabolism in mammalian photoreceptor inner and outer segments

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

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