Toxicity and Efficacy Evaluation of an Adeno-Associated Virus Vector Expressing Codon-Optimized RPGR Delivered by Subretinal Injection in a Canine Model of X-linked Retinitis Pigmentosa.

Autor: Dufour VL; Division of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Cideciyan AV; Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Ye GJ; Applied Genetic Technologies Corporation, Alachua, Florida., Song C; Applied Genetic Technologies Corporation, Alachua, Florida., Timmers A; Applied Genetic Technologies Corporation, Alachua, Florida., Habecker PL; Department of Pathobiology, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania., Pan W; Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Weinstein NM; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Swider M; Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Durham AC; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Ying GS; Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Robinson PM; Applied Genetic Technologies Corporation, Alachua, Florida., Jacobson SG; Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Knop DR; Applied Genetic Technologies Corporation, Alachua, Florida., Chulay JD; Applied Genetic Technologies Corporation, Alachua, Florida., Shearman MS; Applied Genetic Technologies Corporation, Alachua, Florida., Aguirre GD; Division of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Beltran WA; Division of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jazyk: angličtina
Zdroj: Human gene therapy [Hum Gene Ther] 2020 Feb; Vol. 31 (3-4), pp. 253-267. Date of Electronic Publication: 2020 Feb 06.
DOI: 10.1089/hum.2019.297
Abstrakt: Applied Genetic Technologies Corporation (AGTC) is developing a recombinant adeno-associated virus (rAAV) vector AGTC-501, also designated rAAV2tYF-GRK1- hRPGRco , to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase regulator ( RPGR ) gene. The vector contains a codon-optimized human RPGR cDNA ( hRPGRco ) driven by a photoreceptor-specific promoter (G protein-coupled receptor kinase 1 [GRK1]), and is packaged in an AAV2 capsid variant with three surface tyrosine residues changed to phenylalanine (AAV2tYF). We conducted a toxicity and efficacy study of this vector administered by subretinal injection in the naturally occurring RPGR mutant (X-linked progressive retinal atrophy 2 [XLPRA2]) dog model. Sixteen RPGR mutant dogs divided into four groups of three to five animals each received either a subretinal injection of 0.07 mL of AGTC-501 at low (1.2 × 10 11 vector genome [vg]/mL), mid (6 × 10 11 vg/mL), or high dose (3 × 10 12 vg/mL), or of vehicle control in the right eye at early-stage disease. The left eye remained untreated. Subretinal injections were well tolerated and were not associated with systemic toxicity. Electroretinography, in vivo retinal imaging, and histological analysis showed rescue of photoreceptor function and structure in the absence of ocular toxicity in the low- and mid-dose treatment groups when compared with the vehicle-treated group. The high-dose group showed evidence of both photoreceptor rescue and posterior segment toxicity. These results support the use of AGTC-501 in clinical studies with patients affected with XLRP caused by RPGR mutations and define the no-observed-adverse-effect level at 6 × 10 11 vg/mL.
Databáze: MEDLINE
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