Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9

D Dalkara, LC Byrne, T Lee, NV Hoffmann, DV Schaffer… - Gene therapy, 2012 - nature.com
D Dalkara, LC Byrne, T Lee, NV Hoffmann, DV Schaffer, JG Flannery
Gene therapy, 2012nature.com
Delivery of therapeutic genes to a large region of the retina with minimal damage from
intraocular surgery is a central goal of treatment for retinal degenerations. Recent studies
have shown that AAV9 can reach the central nervous system (CNS) and retina when
administered systemically to neonates, which is a promising strategy for some retinal
diseases. We investigated whether the retinal transduction efficiency of systemically
delivered AAV9 could be improved by mutating capsid surface tyrosines, previously shown …
Abstract
Delivery of therapeutic genes to a large region of the retina with minimal damage from intraocular surgery is a central goal of treatment for retinal degenerations. Recent studies have shown that AAV9 can reach the central nervous system (CNS) and retina when administered systemically to neonates, which is a promising strategy for some retinal diseases. We investigated whether the retinal transduction efficiency of systemically delivered AAV9 could be improved by mutating capsid surface tyrosines, previously shown to increase the infectivity of several AAV vectors. Specifically, we evaluated retinal transduction following neonatal intravascular administration of AAV9 vectors containing tyrosine to phenylalanine mutations at two highly conserved sites. Our results show that a novel, double tyrosine mutant of AAV9 significantly enhanced gene delivery to the CNS and retina, and that gene expression can be restricted to rod photoreceptor cells by incorporating a rhodopsin promoter. This approach provides a new methodology for the development of retinal gene therapies or creation of animal models of neurodegenerative disease.
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