In Contrast to AAV-Mediated Cntf Expression, AAV-Mediated Gdnf Expression Enhances Gene Replacement Therapy in Rodent Models of Retinal Degeneration

Abstract

While AAV- and lentivirus-mediated gene replacement therapy can produce structural and functional improvements in various animal models of inherited retinal degeneration, this approach often has very limited effects on the rate of photoreceptor cell loss. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) have been shown to prolong photoreceptor survival in rodent models of retinal degeneration, but AAV-mediated Cntf expression also results in suppression of electrophysiological responses from the retina. In this study using mice, we show that while the deleterious effects mediated by CNTF are dose-dependent, administering a dose of CNTF that does not adversely affect retinal function precludes its ability to delay photoreceptor cell death. In evaluating GDNF as a neuroprotective agent, we show that AAV-mediated Gdnf expression does not produce adverse effects similar to those of CNTF. In addition, we demonstrate the ability of AAV-mediated delivery of Gdnf to slow cell death in two rodent models of retinitis pigmentosa and to enhance retinal function in combination with the relevant gene replacement therapy. These data show for the first time that a combination of these approaches can provide enhanced rescue over gene replacement or growth factor therapy alone.

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

“…Indeed, some detrimental effects have been reported following systemic CNTF injection, such as induction of cachexia in mice 27 or dose-dependent deleterious effects of secreted CNTF in a mouse model of retinal degeneration. 28 Thus, expression of CNTF by the appropriate cell type may be crucial to obtain the beneficial effects of this cytokine; among them, the stimulation of nerve regeneration. In contrast to previous works, we did not add any secretion signal to our construct to promote natural expression and release of CNTF by Schwann cells.…”

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

“…32,33 Of course, increased transduction and stronger transgene expression from gene therapy applications may not necessarily lead to better outcomes, and there is likely to be a fine balance between therapeutic and detrimental expression levels, especially for genes that encode secretable proteins. [34][35][36] This should also be taken into account when choosing promoters that may increase the specificity of transgene expression [37][38][39] and when designing vector systems that allow the temporal regulation of transgene expression. [40][41][42][43] Although comparable in terms of overall transduction efficiency, the tropism profile between rAAV2/2 and rAAV2/6 was considerably different.…”

Gene-based therapies for dominantly inherited retinopathies

“…For example, possible cytotoxic dose-related effects have been observed in preclinical studies with ciliary neurotrophic factor. 64,65 An alternative therapeutic approach relevant to dominant retinopathies under consideration is the modulation of oxidative damage in the degenerating retina. As rod photoreceptor cells die in a retina undergoing a progressive rod-cone dystrophy, remaining cone photoreceptor cells may be subjected to increasing levels of oxygen promoting oxidative damage to cones.…”