Treatment of ocular disorders by gene therapy

Solinís, Maria Ángelés; Pozo-Rodríguez, Ana del; Apaolaza, Paola S.; Rodríguez-Gascón, Alicia

doi:10.1016/j.ejpb.2014.12.022

Cited by 70 publications

(88 citation statements)

References 157 publications

(184 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. Thus, a non-gene-specific rescue strategy (11,12) to increase biosynthetic fuel and survival by reprogramming of glycolysis is highly desirable.…”

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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“…131,132 Moreover, researchers in the burgeoning fields of gene and stem cell therapies are reporting encouraging results for ameliorating the effects of glaucoma, with these modalities likely yielding novel therapeutic options in the upcoming years. [133][134][135] SUMMARY Glaucoma is a painful and blinding group of diseases with no cure. Currently, treatment is aimed at chronically managing the condition, with an ultimate goal of a comfortable and preferably visual eye.…”

Section: Emerging Drug-delivery Platformsmentioning

confidence: 99%

Medical Treatment of Primary Canine Glaucoma

Alario¹,

Strong

Pizzirani

2015

Veterinary Clinics of North America: Small Animal Practice

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“…5 Gene therapy aims at treating, curing, or preventing disease by delivering genes into the eyes; however, current therapies are primarily experimental, with most human clinical trials still in the research phase. 6 For patients only retaining light perception, optogenetic (ie, the use of genetic methods combined with optical technology to achieve retinal neuron function) and stem cell therapies are promising strategies for improving or restoring vision. 7 …”

mentioning

confidence: 99%

Electrical Stimulation as a Means for Improving Vision

Sehic

Guo

Cho

et al. 2016

The American Journal of Pathology

134

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Evolving research has provided evidence that noninvasive electrical stimulation (ES) of the eye may be a promising therapy for either preserving or restoring vision in several retinal and optic nerve diseases. In this review, we focus on minimally invasive strategies for the delivery of ES and accordingly summarize the current literature on transcorneal, transorbital, and transpalpebral ES in both animal experiments and clinical studies. Various mechanisms are believed to underlie the effects of ES, including increased production of neurotrophic agents, improved chorioretinal blood circulation, and inhibition of proinflammatory cytokines. Different animal models have demonstrated favorable effects of ES on both the retina and the optic nerve. Promising effects of ES have also been demonstrated in clinical studies; however, all current studies have a lack of randomization and/or a control group (sham). There is thus a pressing need for a deeper understanding of the underlying mechanisms that govern clinical success and optimization of stimulation parameters in animal studies. In addition, such research should be followed by large, prospective, clinical studies to explore the full potential of ES. Through this review, we aim to provide insight to guide future research on ES as a potential therapy for improving vision. (Am J Pathol 2016 http://dx

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Treatment of ocular disorders by gene therapy

Cited by 70 publications

References 157 publications

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Medical Treatment of Primary Canine Glaucoma

Electrical Stimulation as a Means for Improving Vision

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