Journal Article

Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations

Sha, Jin, Cideciyan, Artur V., Dufour, Valerie L., Kosyk, Mychajlo S., Boye, Shannon E., Shearman, Mark S., Jacobson, Samuel G., Ying, Gui-Shuang, Ye, Guo-Jie, Peterson, James J., Gamlin, Paul D., Boye, Sanford L., Alexander, John J., Iwabe, Simone, Swider, Malgorzata, Aguirre, Gustavo D., Beltran, William A., Witherspoon, C. Douglas, Hauswirth, William W., Chulay, Jeffrey D., Marinho, Luis Felipe

2017

Overview

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates. Two transgenes were used in RPGR mutant (XLPRA2) dogs under the control of the GRK1 promoter. First was the previously developed stabilized human RPGR (hRPGRstb). Second was a new full-length stabilized and codon-optimized human RPGR (hRPGRco). Long-term (>2 years) studies with an AAV2/5 vector carrying hRPGRstb under control of the GRK1 promoter showed rescue of rods and cones from degeneration and retention of vision. Shorter term (3 months) studies demonstrated comparable preservation of photoreceptors in canine eyes treated with an AAV2/5 vector carrying either transgene under the control of the GRK1 promoter. These results provide the critical molecular components (GRK1 promoter, hRPGRco transgene) to now construct a therapeutic viral vector optimized for RPGR-XLRP patients. Recently, Beltran et al. showed in PNAS that RPGR gene augmentation rescues photoreceptors in a canine model of X-linked retinitis pigmentosa. Now, in this issue of Molecular Therapy, they have optimized the viral vector construct by selecting a promoter that targets primate photoreceptors and a full-length codon-optimized RPGR transgene.

• Publisher: Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
• Subject: AAV / Age / Animals / Blindness / canine model / Carrier Proteins - genetics / Cones / Degeneration / Dependovirus - genetics / Disease / Disease Models, Animal / Dogs / Eye Proteins - genetics / G-Protein-Coupled Receptor Kinase 1 - genetics / Gene Expression / Gene Order / Gene therapy / Genes, Reporter / Genes, X-Linked / Genetic Therapy / Genetic Vectors - genetics / Humans / Illustrators / Immunoglobulins / Interphotoreceptor retinoid-binding protein / Microscopy / Mutation / Original / Phenotype / Photoreceptor Cells, Vertebrate - metabolism / Photoreceptors / Preservation / Primates / Promoter Regions, Genetic / Proteins / Retina / Retina - metabolism / Retinitis / Retinitis pigmentosa / Retinitis Pigmentosa - diagnosis / Retinitis Pigmentosa - genetics / Retinitis Pigmentosa - therapy / Rhodopsin kinase / Rods / RPGR / Transduction, Genetic / Transgenes / Vectors (Biology) / Vision Tests / X-linked retinitis pigmentosa