title: Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 (RP2)-knockout mice by gene replacement therapy.
abstract: Retinal neurodegenerative diseases are especially attractive targets for gene replacement therapy, which appears to be clinically effective for several monogenic diseases. X-linked forms of retinitis pigmentosa (XLRP) are relatively severe blinding disorders, resulting from progressive photoreceptor dysfunction primarily caused by mutations in RPGR or RP2 gene. With a goal to develop gene therapy for the XLRP-RP2 disease, we first performed detailed characterization of the Rp2-knockout (Rp2-KO) mice and observed early-onset cone dysfunction, which was followed by progressive cone degeneration, mimicking cone vision impairment in XLRP patients. The mice also exhibited distinct and significantly delayed falling phase of photopic b-wave of electroretinogram (ERG). Concurrently, we generated a self-complementary adeno-associated viral (AAV) vector carrying human RP2-coding sequence and demonstrated its ability to mediate stable RP2 protein expression in mouse photoreceptors. A long-term efficacy study was then conducted in Rp2-KO mice following AAV-RP2 vector administration. Preservation of cone function was achieved with a wide dose range over 18-month duration, as evidenced by photopic ERG and optomotor tests. The slower b-wave kinetics was also completely restored. Morphologically, the treatment preserved cone viability, corrected mis-trafficking of M-cone opsin and restored cone PDE6 expression. The therapeutic effect was achieved even in mice that received treatment at an advanced disease stage. The highest AAV-RP2 dose group demonstrated retinal toxicity, highlighting the importance of careful vector dosing in designing future human trials. The wide range of effective dose, a broad treatment window and long-lasting therapeutic effects should make the RP2 gene therapy attractive for clinical development.
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Suddhasil
authors.initials: S
authors.lastname: Mookherjee
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Suja
authors.initials: S
authors.lastname: Hiriyanna
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Kayleigh
authors.initials: K
authors.lastname: Kaneshiro
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Linjing
authors.initials: L
authors.lastname: Li
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and.
authors.forename: Peter
authors.initials: P
authors.lastname: Colosi
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and wuzh@mail.nih.gov swaroopa@nei.nih.gov.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, MD, USA and wuzh@mail.nih.gov swaroopa@nei.nih.gov.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000818:Animals; D004596:Electroretinography; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D019204:GTP-Binding Proteins; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D012162:Retinal Degeneration / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*
chemical_list: D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C072178:RP2 protein, human; C508759:RP2 protein, mouse; D019204:GTP-Binding Proteins; D011755:Pyrophosphatases