Gene Therapy of Inherited Retinal Degenerations: Prospects and Challenges

Trapani, Ivana; Banfi, Sandro; Simonelli, Francesca; Surace, Enrico Maria; Auricchio, Alberto

doi:10.1089/hum.2015.030

Cited by 41 publications

(29 citation statements)

References 105 publications

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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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“…Electronic retinal prosthetics such as the Argus II, the only FDA approved treatment for end-stage RP, have been able to restore some visual function to blind patients (Yue et al, 2016). Gene therapy approaches either focus on correcting the inherited defects that cause photoreceptor degeneration (Trapani et al, 2015) or seek to convert surviving neurons in the blind retina into artificial photoreceptors via the expression of optogenetic tools using viral vectors (Busskamp et al, 2010; Lagali et al, 2008). Stem cell-based treatments aim to deliver photoreceptor progenitors or other cells into the blind retina to replace cells lost due to disease (Jayakody et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina

Tochitsky

Helft

Meseguer

et al. 2016

Neuron

112

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Summary Azobenzene photoswitches confer light sensitivity onto retinal ganglion cells (RGCs) in blind mice, making these compounds promising candidates as vision-restoring drugs in humans with degenerative blindness. Remarkably, photosensitization manifests only in animals with photoreceptor degeneration and is absent from those with intact rods and cones. Here we show that P2X receptors mediate the entry of photoswitches into RGCs where they associate with voltage-gated ion channels, enabling light to control action potential firing. All charged photoswitch compounds require permeation through P2X receptors, whose gene expression is upregulated in the blind retina. Photoswitches and membrane-impermeant fluorescent dyes likewise penetrate through P2X receptors to label a subset of RGCs in the degenerated retina. Electrophysiological recordings and mapping of fluorescently-labeled RGC dendritic projections together indicate that photosensitization is highly selective for OFF-RGCs. Hence P2X receptors are a natural conduit allowing cell type-selective and degeneration-specific delivery of photoswitches to restore visual function in blinding disease.

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“…Some clinical trials have shown efficacy, 3–7 showing that the gene therapy approach holds promise for the treatment of neurodegenerative diseases of the brain and spinal cord, 8–10 retina, 11 glioblastomas, 12 and has the potential to enhance repair after neurotrauma to central 13,14 and peripheral 15,16 nervous systems. AAV has been used to deliver nerve growth factor (NGF) in patients with Alzheimer’s disease, neurturin or glial cell-derived neurotrophic factor in Parkinson’s disease, and insulin-like growth factor 1 in amyotrophic lateral sclerosis.…”

Section: Introductionmentioning

confidence: 99%

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

LeVaillant

Sharma

Muhling

et al. 2016

Molecular Therapy - Methods & Clinical Development

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Use of viral vectors to deliver therapeutic genes to the central nervous system holds promise for the treatment of neurodegenerative diseases and neurotrauma. Adeno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells. However, these growth-inducing transgenes are driven by a constitutively active promoter, thus we examined whether long-term AAV-mediated secretion of BDNF or CNTF affected endogenous retinal gene expression. One year after the intravitreal injection of AAV-green fluorescent protein (GFP), bi-cistronic AAV-BDNF-GFP or AAV-CNTF-GFP, mRNA was extracted and analyzed using custom 96 well polymerase chain reaction arrays. Of 93 test genes, 56% showed significantly altered expression in AAV-BDNF-GFP and/or AAV-CNTF-GFP retinas compared with AAV-GFP controls. Of these genes, 73% showed differential expression in AAV-BDNF versus AAV-CNTF injected eyes. To focus on retinal ganglion cell changes, quantitative polymerase chain reaction was undertaken on mRNA (16 genes) obtained from fixed retinal sections in which the ganglion cell layer was enriched. The sign and extent of fold changes in ganglion cell layer gene expression differed markedly from whole retinal samples. Sustained and global alteration in endogenous mRNA expression after gene therapy should be factored into any interpretation of experimental/clinical outcomes, particularly when introducing factors into the central nervous system that require secretion to evoke functionality.

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Gene Therapy of Inherited Retinal Degenerations: Prospects and Challenges

Cited by 41 publications

References 105 publications

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina

Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

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