Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-associated X-linked Retinitis Pigmentosa,American Journal of Ophthalmology

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Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-associated X-linked Retinitis Pigmentosa
American Journal of Ophthalmology ( IF 4.1 ) Pub Date : 2024-06-12 , DOI: 10.1016/j.ajo.2024.05.034
Michel Michaelides ₁ , Cagri G Besirli ₂ , Yesa Yang ₁ , Thales A C DE Guimaraes ₁ , Sui Chien Wong ₃ , Rachel M Huckfeldt ₄ , Jason I Comander ₄ , José-Alain Sahel ₅ , Syed Mahmood Shah ₆ , James J L Tee ₁ , Neruban Kumaran ₇ , Anastasios Georgiadis ₈ , Pansy Minnick ₉ , Robert Zeldin ₈ , Stuart Naylor ₈ , Jialin Xu ₉ , Michael Clark ₉ , Eddy Anglade ₉ , Peggy Wong ₉ , Penny R Fleck ₉ , Albert Fung ₉ , Colleen Peluso ₉ , Angelos Kalitzeos ₁ , Michalis Georgiou ₁₀ , Caterina Ripamonti ₁₁ , Alexander J Smith ₁₂ , Robin R Ali ₁₃ , Alexandria Forbes ₈ , James Bainbridge ₁

Affiliation

From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK.
Kellogg Eye Center (C.G.B.), Ann Arbor, Michigan, USA; Janssen Pharmaceuticals (C.G.B.), Raritan, New Jersey, USA.
From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust (S.C.W.), London, UK.
Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School (R.M.H., J.I.C.), Boston, Massachusetts, USA.
UPMC Eye Center, University of Pittsburgh School of Medicine (J.-A.S., S.M.S.), Pittsburgh, Pennsylvania, USA.
UPMC Eye Center, University of Pittsburgh School of Medicine (J.-A.S., S.M.S.), Pittsburgh, Pennsylvania, USA; Gundersen Health System (S.M.S., R.R.A.), La Crosse, Wisconsin, USA.
Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK; Guy's and St. Thomas' NHS Foundation Trust (N.K.), London, UK.
MeiraGTx (A.G., R.Z., S.N., A.F.), New York, New York, USA.
Janssen Pharmaceuticals (P.M., J.X., M.C., E.A., P.W., P.R.F., A.F., C.P.), Raritan, New Jersey, USA.
From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Moorfields Eye Hospital NHS Foundation Trust (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., N.K., A.K., M.G., J.B.), London, UK; Jones Eye Institute, University of Arkansas for Medical Sciences (M.G.), Little Rock, Arkansas, USA.
Cambridge Research Systems Ltd. (C.R.), Rochester, UK.
From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Centre for Gene Therapy and Regenerative Medicine, King's College London (A.J.S.), London, UK.
From the UCL Institute of Ophthalmology (M.M., Y.Y., T.A.C.G., S.C.W., J.J.L.T., A.K., M.G., A.J.S., R.R.A., J.B.), London, UK; Gundersen Health System (S.M.S., R.R.A.), La Crosse, Wisconsin, USA.

To assess the safety and efficacy of AAV5-hRKp. in participants with retinitis pigmentosa GTPase regulator ()-associated X-linked retinitis pigmentosa (XLRP). Open-label, phase 1/2 dose escalation/expansion study (NCT03252847) Males (≥5 years old) with XLRP- were evaluated. In the dose escalation phase, subretinal AAV5-hRKp. (low: 1.0×10 vg/ml; intermediate: 2.0×10 vg/ml; high: 4.0×10 vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants. AAV5-hRKp. was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation–related AEs responded to corticosteroids. Treatment with AAV5-hRKp. resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52. AAV5-hRKp. demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial.

中文翻译：

1/2 期 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) 基因治疗：RPGR 相关 X 连锁视网膜色素变性的安全性和有效性

评估 AAV5-hRKp 的安全性和有效性。患有色素性视网膜炎 GTP 酶调节因子 () 相关 X 连锁色素性视网膜炎 (XLRP) 的参与者。开放标签、1/2 期剂量递增/扩展研究 (NCT03252847) 对使用 XLRP- 的男性（≥5 岁）进行了评估。在剂量递增阶段，视网膜下 AAV5-hRKp。（低：1.0×10 vg/ml；中：2.0×10 vg/ml；高：4.0×10 vg/ml）给予视力较差的眼睛（n = 10）。对 3 名儿科参与者进行了剂量确认（中间剂量）。在剂量扩展阶段，36 名参与者按 1:1:1 随机分配至立即（低或中剂量）或延迟（对照）治疗。主要结果是安全性。次要疗效结果包括静态视野检查、显微视野检查、视力引导移动性、最佳矫正视力和对比敏感度。对立即治疗参与者的安全性和有效性结果进行了 52 周的评估，对对照参与者的安全性和有效性结果进行了 26 周的评估。 AAV5-hRKp。安全且耐受性良好，没有报告剂量限制事件。大多数不良事件 (AE) 都是短暂的，与手术过程相关，无需干预即可解决。报告了两种严重的 AE，需要立即治疗（视网膜脱离、葡萄膜炎）。报告期外报告了第三次严重 AE（眼压升高）。所有与眼部炎症相关的 AE 均对皮质类固醇有反应。用 AAV5-hRKp 治疗。与延迟组相比，第 26 周时视网膜敏感性和功能性视力得到改善；在第 52 周观察到类似的趋势。AAV5-hRKp。在 52 周内展示了预期且可管理的 AE 特征。安全性和有效性研究结果支持三期试验的调查。

更新日期：2024-06-12

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