A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies

Sorrentino, Francesco Saverio; Gallenga, Carla Enrica; Bonifazzi, C.; Perri, Paolo

doi:10.1038/eye.2016.197

Cited by 55 publications

(59 citation statements)

References 74 publications

(73 reference statements)

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“…RP, a debilitating neurodegenerative disorder, is associated with at least 64 genes encoding mostly rod cell-specific proteins that lead to cell death when improperly formed (56)(57)(58). There is currently no cure available, and although gene therapy interventions recently reached clinical trials, the heterogeneity of gene deficits that cause hereditary neurodegenerative conditions is a fundamental limitation of these studies (26,27,29,(59)(60)(61)(62)(63)(64); this is because the strategy involves a monotherapy, which cannot be used to treat disorders caused by mutations in more than one gene.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

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Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca 2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration , were challenging to interpret because of negative effects on synaptic transmission (45). We therefore altered our approach to limit ablation of Sirt6 to rod photoreceptors with an inducible gene disruption strategy. Using this model, we tested whether upregulation of glycolytic flux through Sirt6 knockout can preserve both rod and cone photoreceptors in a preclinical, Pde6-associated RP model. The Journal of Clinical Investigation R E S E A R C H A R T I C L E ResultsGeneration of experimental and control groups. The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9, 46-48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12). In our report, we propose a similar strategy that improves both survival and function of degenerating rods and cones. We hypothesized that Pde6-associated RP provokes a metabolic aberration in the rod cells that forces them to succumb to the consequences of elevated cGMP and Ca 2+ via cyclic nucleotide-gated (CNG) channels and Na + /Ca 2+ -K + exchangers (36-39). The histone deacetylase sirtuin 6 (SIRT6) is a transcriptional repressor of glycolytic enzymes that has been extensively studied in the context of metabolism and cancer biology (40). Normally, S...

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Section: Discussionmentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

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“…RP is estimated to affect 1 in 4,000 individuals totaling over 2 million individuals wordwide (Sorrentino et al, 2016). The age of onset of RP varies from infancy to late middle age with severe visual impairments detected by age 40–50 (Haim et al, 1992; Parmeggiani, 2011).…”

Section: Retinal Degenerative Diseases (Rdds)mentioning

confidence: 99%

“…RP is a hereditary and genetically heterogeneous with 260 genes and 4,500 mutations identified accounting for less than 50% of RPs, and can be inherited as an autosomal dominant, autosomal recessive, or X-linked trait (Bhattacharya et al, 1984; Farrar et al, 1990; McWilliam et al, 1989; Rosenfeld et al, 1992; Sorrentino et al, 2016). 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).…”

Section: Retinal Degenerative Diseases (Rdds)mentioning

confidence: 99%

“…One advantage to preservation strategies is that the transplantation of allogeneic cells is gene- and mutation- independent. AMD has multiple gene and epidemiological risk factors, and RP has numerous risk variants and loci, which complicates the generation of universal treatments (Fritsche et al, 2016; Sorrentino et al, 2016; Tomany et al, 2004). Supportive cells for preservation techniques are designed to encompass diseases with an array of mutations and risk factors, and could potentially treat a large population of patients.…”

Section: Cell-based Therapeutic Strategies For Rddsmentioning

confidence: 99%

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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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“…Indeed, GWAS have detected dozens of risk loci for other types of common cancer, such as non‐familial colorectal carcinoma and non‐familial breast cancer . Moreover, retinitis pigmentosa, one of the most genetically complex diseases known today, has approximately 4500 causative mutations in more than 250 genes . Because we have no reason to believe that lung cancer is a simpler disease than other common cancers or non‐cancer diseases such as retinitis pigmentosa, we hope that new developments in artificial intelligence and in methods to detect complex interactions in association studies will shed light on the genetic factors modulating individual risk and outcome in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Complex genetic control of lung tumorigenesis in resistant mice strains

et al. 2017

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The SM/J mouse strain is resistant to chemically‐induced lung tumorigenesis despite having a haplotype, in the pulmonary adenoma susceptibility locus (Pas1) locus, that confers tumor susceptibility in other strains. To clarify this inconsistent genotype‐phenotype correlation, we crossed SM/J mice with another resistant strain and conducted genome‐wide linkage analysis in the (C57BL/6J × SM/J)F2 progeny exposed to urethane to induce lung tumors. Overall, >80% of F2 mice of both sexes developed from 1 to 20 lung tumors. Genotyping of 372 F2 mice for 744 informative non‐redundant SNPs dispersed over all autosomal chromosomes revealed four quantitative trait loci (QTLs) affecting lung tumor multiplicity, on chromosomes 3 (near rs13477379), 15 (rs6285067), 17 (rs33373629) and 18 (rs3706601), all with logarithm of the odds (LOD) scores >5. Four QTLs modulated total lung tumor volume, on chromosome 3 (rs13477379), 10 (rs13480702), 15 (rs6285067) and 17 (rs3682923), all with LOD scores >4. No QTL modulating lung tumor multiplicity or total volume was detected in Pas1 on chromosome 6. The present study demonstrates that the SM/J strain carries, at the Pas1 locus, the resistance allele: a finding that will facilitate identification of the Pas1 causal element. More generally, it demonstrates that lung tumorigenesis is under complex polygenic control even in a pedigree with low susceptibility to this neoplasia, suggesting that the genetics of lung tumorigenesis is much more complex than evidenced by the pulmonary adenoma susceptibility and resistance loci that have, so far, been mapped in a small number of crosses between a few inbred strains.

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A challenge to the striking genotypic heterogeneity of retinitis pigmentosa: a better understanding of the pathophysiology using the newest genetic strategies

Cited by 55 publications

References 74 publications

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

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

Complex genetic control of lung tumorigenesis in resistant mice strains

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