Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.
Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.
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DOI：
10.1038/s41591-022-01755-w
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发表时间：
2022-05
期刊：
影响因子：
82.9
通讯作者：
Girach, Aniz
中科院分区：
文献类型：
--
作者：
Russell, Stephen R.;Drack, Arlene, V;Cideciyan, Artur, V;Jacobson, Samuel G.;Leroy, Bart P.;Van Cauwenbergh, Caroline;Ho, Allen C.;Dumitrescu, Alina, V;Han, Ian C.;Martin, Mitchell;Pfeifer, Wanda L.;Sohn, Elliott H.;Walshire, Jean;Garafalo, Alexandra, V;Krishnan, Arun K.;Powers, Christian A.;Sumaroka, Alexander;Roman, Alejandro J.;Vanhonsebrouck, Eva;Jones, Eltanara;Nerinckx, Fanny;De Zaeytijd, Julie;Collin, Rob W. J.;Hoyng, Carel;Adamson, Peter;Cheetham, Michael E.;Schwartz, Michael R.;den Hollander, Wilhelmina;Asmus, Friedrich;Platenburg, Gerard;Rodman, David;Girach, Aniz
CEP 290相关的Leber先天性黑蒙10型（LCA 10）是一种导致儿童失明的视网膜疾病。Sepofarsen是一种靶向CEP 290基因中c.2991+ 1655 A>G变体的RNA反义寡核苷酸，用于治疗LCA 10。在这项开放标签、1b/2期（NCT 03140969）、12个月、多中心、多次给药、剂量递增试验中，6例成人患者和5例儿童患者在视力最差眼接受了≤4剂玻璃体内sepofarsen。主要目的是通过眼部不良事件（AE）的频率和严重程度评价sepofarsen的安全性和耐受性;次要目的是通过功能结局的变化评价药代动力学和疗效。6例患者接受Sepofarsen 160 µg/80 µg，5例患者接受Sepofarsen 320 µg/160 µg。11例患者中有10例（90.9%）接受治疗的眼睛发生眼部AE（160 µg/80 µg组5/6例; 320 µg/160 µg组5/5例），而未接受治疗的11例患者中有1例（9.1%）发生眼部AE;大多数患者的严重程度为轻度且呈剂量依赖性。8例患者发生白内障，其中6例（75.0%）被归类为严重（160 µg/80 µg组2/3例; 320 µg/160 µg组4/5例），因为需要更换透镜。由于160 µg/80 µg组显示出更好的获益-风险特征，因此停止或不开始使用更高剂量。报告了视力和视网膜敏感度的统计学显著改善（事后分析）。本试验中报告的可管理的安全性特征和改善支持继续开发sepofarsen。在Leber先天性黑蒙10型患者中玻璃体内注射反义寡核苷酸sepofarsen显示出可管理的安全性，眼部不良事件具有剂量依赖性，并实现了视觉功能的有意义的改善。
CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development. Intravitreal administration of the antisense oligonucleotide sepofarsen in patients with Leber congenital amaurosis type 10 showed a manageable safety profile, ocular adverse events being dose dependent, and achieved meaningful improvements of visual function.
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DOI：
10.1016/j.omtn.2018.07.010
发表时间：
2018-09-07
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Dulla K;Aguila M;Lane A;Jovanovic K;Parfitt DA;Schulkens I;Chan HL;Schmidt I;Beumer W;Vorthoren L;Collin RWJ;Garanto A;Duijkers L;Brugulat-Panes A;Semo M;Vugler AA;Biasutto P;Adamson P;Cheetham ME
通讯作者：
Cheetham ME
DOI：
10.1038/mtna.2012.21
发表时间：
2012-06-26
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
影响因子：
82.9
作者：
Cideciyan AV;Jacobson SG;Ho AC;Garafalo AV;Roman AJ;Sumaroka A;Krishnan AK;Swider M;Schwartz MR;Girach A
通讯作者：
Girach A
影响因子：
1.6
作者：
Erdogan, Gurkan;Gunay, Betul Onal;Ergin, Ahmet
通讯作者：
Ergin, Ahmet
DOI：
10.1097/iae.0000000000000144
发表时间：
2014-09
期刊：
Retina (Philadelphia, Pa.)
影响因子：
--
作者：
Collison FT;Fishman GA;McAnany JJ;Zernant J;Allikmets R
通讯作者：
Allikmets R