Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa.
Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.
Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. wbeltran@vet.upenn.edu
William A
WA
Beltran
Artur V
AV
Cideciyan
Alfred S
AS
Lewin
Simone
S
Iwabe
Hemant
H
Khanna
Alexander
A
Sumaroka
Vince A
VA
Chiodo
Diego S
DS
Fajardo
Alejandro J
AJ
Román
Wen-Tao
WT
Deng
Malgorzata
M
Swider
Tomas S
TS
Alemán
Sanford L
SL
Boye
Sem
S
Genini
Anand
A
Swaroop
William W
WW
Hauswirth
Samuel G
SG
Jacobson
Gustavo D
GD
Aguirre
D000818:Animals; D001766:Blindness / Q000235:genetics* / Q000628:therapy*; D004285:Dogs; D005136:Eye Proteins / Q000235:genetics / Q000627:therapeutic use; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy; D005838:Genotype; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D055355:Opsins / Q000378:metabolism; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D021381:Protein Transport; D051245:Retinal Bipolar Cells / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000628:therapy*
D005136:Eye Proteins; D055355:Opsins; C099929:RPGR protein, human