Pharmacological Enhancement of ex vivo Gene Therapy Neuroprotection in a Rodent Model of Retinal Degeneration

Gregory-Evans, Kevin; Po, Kelvin; Chang, Fumin; Gregory‐Evans, Cheryl Y.

doi:10.1159/000325730

Cited by 13 publications

(9 citation statements)

References 90 publications

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“…56 We recently used a combinatorial approach of aminoglycoside read-through to treat the underlying genetic defect in the rat S334ter model coupled with glialderived neurotrophic factor neuroprotection, which fully rescued the retinal degeneration, whereas individually we found that these treatments had limited efficacy. 57 In this study, we have shown that RIP3-dependent necroptosis is the underlying molecular cause of cone cell death in the pde6c w59 model, whereas rod cells are dying via caspase-dependent apoptosis. Thus, development of effective treatment strategies for retinal degeneration affecting both rods and cones requires components that target both the primary genetic deficit and the secondary bystander cell loss.…”

Section: Discussionmentioning

confidence: 73%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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Section: Discussionmentioning

confidence: 73%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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“…This previously published data with gentamicin in conjunction with the present significant elevated read‐through efficiency of NB54 or PTC124 compared to that of gentamicin, suggests that these two TRIDs should induce the recovery of sufficient amounts of functional harmonin protein to combat or at least slow down the retinal degeneration in USH1 patients. Moreover a combined treatment of TRIDs with neurotropic factors may have an even higher capacity to treat nonsense mutation‐based retinal diseases as indicated by Gregory‐Evans et al (2011). Finally, in further investigations, the co‐administration of poly‐ L ‐aspartic acid (PAA), which has been shown to enhance aminoglycoside‐induced read‐through and decrease aminoglycoside‐induced toxicity, may provide an additional approach to enhance the efficacy of aminoglycoside variants NB30 and NB54 for the treatment of USH1 (Swan et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

A comparative evaluation of NB30, NB54 and PTC124 in translational read‐through efficacy for treatment of an USH1C nonsense mutation

et al. 2012

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Translational read-through-inducing drugs (TRIDs) promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. Here, we compare for the first time the relative efficacies of new-generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read-through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf-blindness. We quantify read-through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read-through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read-through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full-length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read-through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation-based retinal disorders.

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“…The concept of neuroprotection by inhibiting cell death has emerged over the last decade and a range of factors, such as ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and basic fibroblast growth factor (bFGF), have been identified as potential neuroprotectants. Major concerns with the neurotrophic factors are either they are too large to cross the blood-retinal barrier (BRB) or are associated with undesirable systemic complication [20]. Cell-based therapies, with their paracrine effects, have overcome the complexities associated with systemic delivery of these molecules.…”

Section: Eye Disordersmentioning

confidence: 99%