A Multiple-Site, Phase 1/2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing Retinoschisin (rAAV2tYF-CB-hRS1) in Patients With X-linked Retinoschisis

This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector expressing retinoschisin (rAAV2tYF-CB-hRS1) in patients with X-linked retinoschisis. Up to 27 participants will be enrolled and 3 dose levels will be evaluated in a dose escalation format.

开始日期2015-05-01

申办/合作机构

Beacon Therapeutics (USA), Inc.

100 项与 Adeno-associated viral vector expressing human retinoschisin-1 gene therapy(Applied Genetic Technologies Corp.) 相关的临床结果

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100 项与 Adeno-associated viral vector expressing human retinoschisin-1 gene therapy(Applied Genetic Technologies Corp.) 相关的专利（医药）

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项与 Adeno-associated viral vector expressing human retinoschisin-1 gene therapy(Applied Genetic Technologies Corp.) 相关的文献（医药）

2022-12-01·Ophthalmology Retina

Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis

Article

作者: Weng, Christina Y. ; Scholle, Tahira ; Birch, David G. ; Chulay, Jeffrey ; Yang, Paul ; Moore, Anthony ; Comander, Jason I. ; Birch, David ; Pennesi, Mark Edward ; Mettu, Priyatham ; Bressler, Neil ; Stewart, Jay ; Pennesi, Mark ; Feinsod, Matthew ; Moore, Anthony T. ; Comander, Jason ; Baker, Laura ; Vajzovic, Lejla ; Jayasundera, K. Thiran ; Iannaccone, Alessandro ; Channa, Roomasa ; Jayasundera, Thiran ; Lam, Byron ; Bennett, Lea ; Halliman, Deanine

PURPOSETo 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.DESIGNOpen-label, phase I/II dose-escalation clinical trial.SUBJECTSTwenty-two adults and 5 children with X-linked retinoschisis (XLRS), aged 10 to 79 years, were enrolled.METHODSThe 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 MEASURESThe 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).RESULTSThe 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.CONCLUSIONSGene 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.

2020-02-01·Human Gene Therapy2区 · 医学

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

2区 · 医学

Article

作者: Ying, Gui-Shuang ; Dufour, Valérie L. ; Swider, Malgorzata ; Weinstein, Nicole M. ; Robinson, Paulette M. ; Cideciyan, Artur V. ; Aguirre, Gustavo D. ; Durham, Amy C. ; Chulay, Jeffrey D. ; Shearman, Mark S. ; Timmers, Adrian ; Ye, Guo-jie ; Pan, Wei ; Beltran, William A. ; Habecker, Perry L. ; Knop, David R. ; Jacobson, Samuel G. ; Song, Chunjuan

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 × 10¹¹ vector genome [vg]/mL), mid (6 × 10¹¹ vg/mL), or high dose (3 × 10¹² 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 × 10¹¹ vg/mL.

2015-09-01·Human Gene Therapy Clinical Development3区 · 医学

Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin

3区 · 医学

Article

作者: Sharma, Alok K. ; McGill, Trevor ; Sonnentag, Peter ; Chulay, Jeffrey D. ; Miller, Paul E. ; Howard, Kellie ; Knop, David R. ; Stoddard, Jonathan ; Neuringer, Martha ; Budzynski, Ewa ; Ye, Guo-Jie ; Ver Hoeve, James N.

Applied Genetic Technologies Corporation is developing rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus (rAAV) vector for treatment of X-linked retinoschisis (XLRS), an inherited retinal disease characterized by splitting (schisis) of retinal layers causing poor vision. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-CB-hRS1 in normal cynomolgus macaques. Three groups of male animals (n = 6 per group) received an intravitreal injection in one eye of either vehicle, or rAAV2tYF-CB-hRS1 at one of two dose levels (4 × 10(10) or 4 × 10(11) vg/eye). Half the animals were sacrificed after 14 days and the others after 91 or 115 days. The intravitreal injection procedure was well tolerated in all groups. Serial ophthalmic examinations demonstrated a dose-related anterior and posterior segment inflammatory response that improved over time. There were no test article-related effects on intraocular pressure, electroretinography, visual evoked potential, hematology, coagulation, clinical chemistry, or gross necropsy observations. Histopathological examination demonstrated minimal or moderate mononuclear infiltrates in 6 of 12 vector-injected eyes. Immunohistochemical staining showed RS1 labeling of the ganglion cell layer at the foveal slope in vector-injected eyes at both dose levels. Serum anti-AAV antibodies were detected in 4 of 6 vector-injected animals at the day 15 sacrifice and all vector-injected animals at later time points. No animals developed antibodies to RS1. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-CB-hRS1 in clinical studies in patients with XLRS.

100 项与 Adeno-associated viral vector expressing human retinoschisin-1 gene therapy(Applied Genetic Technologies Corp.) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
视网膜劈裂	临床2期	美国	Beacon Therapeutics (USA), Inc.	2015-05-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02416622 (CTgov)	临床1/2期	视网膜劈裂	27	rAAV2tYF-CB-hRS1 (rAAV2tYF-CB-hRS1 1 x 10^11 vg Per Eye)	積積網網夢衊鹽膚膚襯(糧憲蓋夢築繭鬱選壓鑰) = 蓋醖膚壓網蓋餘獵窪餘鹽憲顧糧繭窪鏇製糧齋 (積網艱憲窪衊鏇獵淵淵, 遞繭網構鹹選鹹鬱衊觸 ~ 憲製鹽憲襯壓構觸繭網) 更多	-	2020-07-01
				rAAV2tYF-CB-hRS1 (rAAV2tYF-CB-hRS1 3 x 10^11 vg Per Eye)	積積網網夢衊鹽膚膚襯(糧憲蓋夢築繭鬱選壓鑰) = 遞憲獵憲構齋觸蓋襯觸鹽憲顧糧繭窪鏇製糧齋 (積網艱憲窪衊鏇獵淵淵, 獵網築範鹽簾醖繭蓋鹽 ~ 構顧觸艱鹹窪願衊鹹鹽) 更多