PMID- 35781068 OWN - NLM STAT- MEDLINE DCOM- 20221209 LR - 20230104 IS - 2468-6530 (Electronic) IS - 2468-6530 (Linking) VI - 6 IP - 12 DP - 2022 Dec TI - Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis: 1-Year Clinical Results. PG - 1130-1144 LID - S2468-6530(22)00320-7 [pii] LID - 10.1016/j.oret.2022.06.013 [doi] AB - PURPOSE: To evaluate the safety and efficacy of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin (RS1), in individuals with retinal disease caused by mutations in the RS1 gene. DESIGN: Open-label, phase I/II dose-escalation clinical trial. SUBJECTS: Twenty-two adults and 5 children with X-linked retinoschisis (XLRS), aged 10 to 79 years, were enrolled. METHODS: The participants received an intravitreal (IVT) injection of rAAV2tYF-CB-hRS1, at 1 of 3 dose levels, in the poorer-seeing eye and were followed up for a minimum of 1 year after treatment. MAIN OUTCOME MEASURES: The primary safety measures were local (ocular) or systemic (nonocular) adverse events (AEs) during the 12-month period after study agent administration. Efficacy was assessed based on measures of best-corrected visual acuity (BCVA), schisis cavity volume, static perimetry visual field testing, and electroretinography (ERG). RESULTS: The IVT administration of rAAV2tYF-CB-hRS1 was generally safe at each of the dose levels. There were no AEs resulting in early termination, and no dose-limiting toxicities were reported. The most common ocular AEs observed were related to ocular inflammation (blurred vision, visual impairment, and the presence of vitreous cells, keratic precipitates, vitreous floaters, anterior chamber cells, and vitreous haze). Ocular inflammation was generally either mild or moderate in severity and responsive to standard immunosuppressive therapy, except in 3 participants (all in the highest-dose group) who developed chronic uveitis, which required prolonged therapy. Two patients experienced retinal detachments. There was no overall improvement in BCVA, visual fields, or ERG in the study eye compared with that in the fellow eye for any dose group. Variable changes in the cystic cavity volume over time were similar in the study and fellow eyes. CONCLUSIONS: Gene augmentation therapy with rAAV2tYF-CB-hRS1 for XLRS was generally safe and well tolerated but failed to demonstrate a measurable treatment effect. The clinical trial is ongoing through 5 years of follow-up to assess its long-term safety. CI - Copyright (c) 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Pennesi, Mark Edward AU - Pennesi ME AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. Electronic address: pennesim@ohsu.edu. FAU - Yang, Paul AU - Yang P AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Birch, David G AU - Birch DG AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Weng, Christina Y AU - Weng CY AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Moore, Anthony T AU - Moore AT AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Iannaccone, Alessandro AU - Iannaccone A AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Comander, Jason I AU - Comander JI AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Jayasundera, Thiran AU - Jayasundera T AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. FAU - Chulay, Jeffrey AU - Chulay J AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. CN - XLRS-001 Study Group AD - Casey Eye Institute, Oregon Health & Sciences University, Portland, Oregon; Retina Foundation of the Southwest, Dallas, Texas; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; University of California San Francisco, San Francisco, California; Duke Eye Center, Duke Medical Center, Durham, North Carolina; Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan; Applied Genetic Technologies Corporation, Alachua, Florida. LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220630 PL - United States TA - Ophthalmol Retina JT - Ophthalmology. Retina JID - 101695048 RN - 0 (Eye Proteins) SB - IM MH - Adult MH - Child MH - Humans MH - Dependovirus/genetics MH - Eye Proteins/genetics MH - Genetic Vectors MH - Inflammation MH - Intravitreal Injections MH - Retina MH - *Retinoschisis/diagnosis/genetics/therapy OTO - NOTNLM OT - Gene therapy OT - Retina OT - X-linked retinoschisis FIR - Chulay, Jeffrey IR - Chulay J FIR - Halliman, Deanine IR - Halliman D FIR - Feinsod, Matthew IR - Feinsod M FIR - Pennesi, Mark IR - Pennesi M FIR - Yang, Paul IR - Yang P FIR - Birch, David IR - Birch D FIR - Bennett, Lea IR - Bennett L FIR - Weng, Christina Y IR - Weng CY FIR - Scholle, Tahira IR - Scholle T FIR - Channa, Roomasa IR - Channa R FIR - Baker, Laura IR - Baker L FIR - Stewart, Jay IR - Stewart J FIR - Moore, Anthony IR - Moore A FIR - Iannaccone, Alessandro IR - Iannaccone A FIR - Mettu, Priyatham IR - Mettu P FIR - Vajzovic, Lejla IR - Vajzovic L FIR - Jayasundera, K Thiran IR - Jayasundera KT FIR - Comander, Jason IR - Comander J FIR - Bressler, Neil IR - Bressler N FIR - Lam, Byron IR - Lam B EDAT- 2022/07/06 06:00 MHDA- 2022/12/07 06:00 CRDT- 2022/07/05 08:48 PHST- 2022/04/24 00:00 [received] PHST- 2022/06/21 00:00 [revised] PHST- 2022/06/22 00:00 [accepted] PHST- 2022/07/06 06:00 [pubmed] PHST- 2022/12/07 06:00 [medline] PHST- 2022/07/05 08:48 [entrez] AID - S2468-6530(22)00320-7 [pii] AID - 10.1016/j.oret.2022.06.013 [doi] PST - ppublish SO - Ophthalmol Retina. 2022 Dec;6(12):1130-1144. doi: 10.1016/j.oret.2022.06.013. Epub 2022 Jun 30.