Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies.
Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies.
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DOI：
10.3390/medicina57010064
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发表时间：
2021-01-12
期刊：
影响因子：
--
通讯作者：
Vingolo EM
中科院分区：
文献类型：
--
作者：
Abbouda A;Avogaro F;Moosajee M;Vingolo EM
背景与目的：无脉络膜症（Choroideremia，CHM）是一种X连锁隐性遗传性脉络膜视网膜营养不良，由CHM基因突变引起。基因治疗已进入后期临床试验阶段，尽管结果不一。这篇综述总结了I/II期CHM基因治疗试验的结果，并介绍了其他潜在的实验性治疗方法。材料与方法：进行Medline（美国国家医学图书馆，Bethesda，MD，USA）检索，以识别描述可用于CHM的基因疗法治疗的所有文章。结果如下：纳入了5项I/II期临床试验，这些试验报告了在CHM患者中视网膜下注射腺相关病毒Rab护送蛋白1（AAV2.REP 1）载体。牛津研究（NCT 01461213）纳入了14例患者;报告了早期治疗糖尿病视网膜病变研究（ETDRS）字母的中位增益为5.5 ± 6.8 SD（−6 min，18 max）。Tubingen研究（NCT 02671539）纳入了6例患者;仅1例患者的ETDRS改善了17个字母。阿尔伯塔研究（NCT 02077361）入组了6例患者，除1例患者获得15个ETDRS字母外，报告了最小的视力变化。6例患者入组迈阿密试验（NCT 02553135），报告ETDRS字母的中位增益为2 ± 4 SD（−1 min，10 max）。费城研究（NCT 02341807）纳入了10例患者;在1年随访时，所有患者的最佳矫正视力（BCVA）均恢复至基线，但1例患者的ETDRS字母较基线为-17。总体而言，40例患者入组试验，34例患者接受了2年随访，ETDRS信件中的中位增益为1.5 ± 7.2 SD（−14 min，18 max）。结论：CHM基因治疗后的主要终点BCVA显示了边际改善，但试验间存在差异。优化手术技术和术前、术中和术后免疫抑制剂管理，以最大限度地减少任何不良眼部炎症事件，可降低并发症的发生率。理想的治疗窗口需要解决，以确保必要的细胞类型被充分转导，最大限度地减少病毒毒性，以延长长期转基因潜力。长期疗效将通过正在进行的研究来解决。
Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (−6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (−1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had −17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (−14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies.
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DOI：
10.1038/s41433-020-0974-1
发表时间：
2021-03
期刊：
Eye (London, England)
影响因子：
--
作者：
Hagag AM;Mitsios A;Narayan A;Abbouda A;Webster AR;Dubis AM;Moosajee M
通讯作者：
Moosajee M
影响因子：
4.4
作者：
Aleman, Tomas S.;Cideciyan, Artur V.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.
影响因子：
4.4
作者：
Fingler, Jeff;Readhead, Carol;Fraser, Scott E.
通讯作者：
Fraser, Scott E.
影响因子：
3.4
作者：
Guerin, K.;Gregory-Evans, C. Y.;Flannery, John G.
通讯作者：
Flannery, John G.
影响因子：
4.4
作者：
Duncan, Jacque L.;Zhang, Yuhua;Roorda, Austin
通讯作者：
Roorda, Austin