title: Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease.
abstract: Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; wbeltran@vet.upenn.edu cideciya@mail.med.upenn.edu gda@vet.upenn.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Beltran
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104; wbeltran@vet.upenn.edu cideciya@mail.med.upenn.edu gda@vet.upenn.edu.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Simone
authors.initials: S
authors.lastname: Iwabe
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Swider
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Mychajlo S
authors.initials: MS
authors.lastname: Kosyk
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Kendra
authors.initials: K
authors.lastname: McDaid
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Inna
authors.initials: I
authors.lastname: Martynyuk
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Gui-Shuang
authors.initials: GS
authors.lastname: Ying
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: James
authors.initials: J
authors.lastname: Shaffer
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610;
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Deng
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610;
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610.
authors.forename: Alfred S
authors.identifier: http://orcid.org/0000-0002-4192-9727
authors.initials: AS
authors.lastname: Lewin
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610;
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; wbeltran@vet.upenn.edu cideciya@mail.med.upenn.edu gda@vet.upenn.edu.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D012162:Retinal Degeneration / Q000503:physiopathology / Q000628:therapy*; D014785:Vision, Ocular
keywords: RPGR; XLRP; gene therapy; late stage; retinal degeneration