Long-Term Inducible Gene Expression in the Eye via Adeno-Associated Virus Gene Transfer in Nonhuman Primates

Abstract

Adeno-associated viral gene therapy has shown promise for the treatment of inherited and degenerative diseases in a variety of animal models. Some of the most dramatic results have been obtained in the field of ocular gene therapy, where efficacy has been tremendous in inherited and acquired retinal disorders. For the promise of this approach to be realized it will be necessary to create vectors capable of pharmacologic or physiologic regulation of the transgene. We describe in this paper a dimerizer-inducible viral expression system that is able to reproducibly drive expression of the reporter gene erythropoietin in the eyes of nonhuman primates over a period of 2.5 years. The expression profiles were characterized by minimal basal expression in the absence of inducer and dose-responsive maximal expression in the presence of inducer drug.

Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model

“…The vascular changes in trVEGF029 differ from two other models in which VEGF was upregulated via a transgene or via intravitreal or subretinal injection of a recombinant adeno-associated virus carrying the gene encoding VEGF (AAV.VEGF) [21,35] with high protein levels leading to severe neovascularisation, an immune reaction and photoreceptor destruction [21,36]. In comparison, moderate VEGF expression in another model induced by AAV.VEGF gene transfer also produced a mild phenotype with features similar to trVEGF029 and with no immune reaction elicited [37].…”

Gene therapy progress and prospects: the eye

“…22 A dimerizer-inducible expression system reproducibly drives reporter gene expression in the retina of nonhuman primates with dose-responsive inducible expression over a period of 2.5 years. 23 Furthermore, tetracycline-inducible expression of interleukin (IL)-10 by a single-vector rAAV system is able to mediate a therapeutic effect in an experimental model of uveitis. 24 An alternative approach is to design a promoter system that is 'vigilant' in its response to a relevant feature of the local tissue environment.…”

AAV-mediated gene therapy for retinal disorders: from mouse to man

“…33 A dimerizer-inducible expression system reproducibly drives dose-responsive inducible reporter gene expression in the retina of nonhuman primates with over a period of 2.5 years. 34 Furthermore, tetracycline-inducible expression of interleukin (IL)-10 by a single-vector rAAV system mediates a therapeutic effect in an experimental model of uveitis. 35 Further improvements in AAV vector design include the cloning of self-complementary genomes.…”