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

Authors
  • Beltran, William A1
  • Cideciyan, Artur V2
  • Boye, Shannon E3
  • Ye, Guo-Jie4
  • Iwabe, Simone5
  • Dufour, Valerie L5
  • Marinho, Luis Felipe5
  • Swider, Malgorzata2
  • Kosyk, Mychajlo S2
  • Sha, Jin2
  • Boye, Sanford L3
  • Peterson, James J3
  • Witherspoon, C Douglas6
  • Alexander, John J7
  • Ying, Gui-Shuang2
  • Shearman, Mark S4
  • Chulay, Jeffrey D4
  • Hauswirth, William W3
  • Gamlin, Paul D6
  • Jacobson, Samuel G2
  • And 1 more
  • 1 Division of Experimental Retinal Therapies, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19014, USA. Electronic address: [email protected]
  • 2 Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
  • 4 Applied Genetic Technologies Corporation, Alachua, FL 32615, USA.
  • 5 Division of Experimental Retinal Therapies, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19014, USA.
  • 6 Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 7 Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30303, USA.
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
Aug 02, 2017
Volume
25
Issue
8
Pages
1866–1880
Identifiers
DOI: 10.1016/j.ymthe.2017.05.004
PMID: 28566226
Source
Medline
Keywords
License
Unknown

Abstract

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.

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