title: Improvement in vision: a new goal for treatment of hereditary retinal degenerations.
abstract: Introduction:Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations inRPE65(retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances.Areas covered:Progress toward human therapy forRPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested.Expert opinion:The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention.
authors.affiliation: University of Pennsylvania, Scheie Eye Institute, Perelman School of Medicine, Department of Ophthalmology , Philadelphia, PA, USA jacobsos@mail.med.upenn.edu.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: University of Pennsylvania, Scheie Eye Institute, Perelman School of Medicine, Department of Ophthalmology , Philadelphia, PA, USA jacobsos@mail.med.upenn.edu.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: University of Pennsylvania, School of Veterinary Medicine, Section of Ophthalmology , Philadelphia, PA, USA.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.affiliation: University of Pennsylvania, Scheie Eye Institute, Perelman School of Medicine, Department of Ophthalmology , Philadelphia, PA, USA jacobsos@mail.med.upenn.edu.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.affiliation: University of Pennsylvania, Scheie Eye Institute, Perelman School of Medicine, Department of Ophthalmology , Philadelphia, PA, USA jacobsos@mail.med.upenn.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.affiliation: University of Florida, Department of Ophthalmology , Gainesville, FL, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Case Western University, School of Medicine, Cleveland Center for Membrane and Structural Biology, Department of Pharmacology , Cleveland, OH, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
keywords: Leber congenital amaurosis; gene therapy; photoreceptors; retina; retinal pigment epithelium; retinoid cycle