Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.
Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.
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DOI：
10.1016/s0140-6736(09)61836-5
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发表时间：
2009-11-07
期刊：
影响因子：
168.9
通讯作者：
Bennett, Jean
中科院分区：
文献类型：
--
作者：
Maguire, Albert M.;High, Katherine A.;Auricchio, Alberta;Wright, J. Fraser;Pierce, Eric A.;Testa, Francesco;Mingozzi, Federico;Bennicelli, Jeannette L.;Ying, Gui-shuang;Rossi, Settimio;Fulton, Ann;Marshall, Kathleen A.;Banfi, Sandra;Chung, Daniel C.;Morgan, Jessica I. W.;Hauck, Bernd;Zelenaia, Olga;Zhu, Xiaosong;Raffini, Leslie;Coppieters, Frauke;De Baere, Elfride;Shindler, Kenneth S.;Volpe, Nicholas J.;Surace, Enrico M.;Acerra, Carmela;Lyubarsky, Arkady;Redmond, T. Michael;Stone, Edwin;Sun, Junwei;McDonnell, Jennifer Wellman;Leroy, Bart P.;Simonelli, Francesca;Bennett, Jean
基因治疗有可能逆转疾病或防止无法治愈的遗传性视网膜变性患者视力进一步恶化。因此，我们进行了一项一期试验，以评估基因治疗对患有莱伯氏先天性黑朦的儿童和成人的视网膜和视觉功能的影响。我们评估了12例（8-44岁）患有rpe65相关Leber先天性黑内障的患者的视网膜和视觉功能，这些患者在视网膜下注射含有编码视网膜色素上皮异质水解酶活性所需蛋白的基因的腺相关病毒（AAV），在低（1·5×1010载体基因组），中（4·8×1010载体基因组）或高剂量（1·5×1011载体基因组）长达2年。AAV2-hRPE65v2耐受性良好，所有患者的主观和客观视力测量（即黑暗适应测量、瞳孔测量、视网膜电图、眼球震颤和走动行为）均持续改善。患者瞳孔对光的反应至少增加了2个对数单位，一个8岁的孩子的对光敏感度几乎与同龄正常视力的人相同。改善最大的是儿童，他们都获得了移动视力。该研究已在ClinicalTrials.gov注册，注册号为NCT00516477。所有患者视力改善的安全性、程度和稳定性支持使用aav介导的基因疗法治疗遗传性视网膜疾病，早期干预可获得最佳潜在收益。费城儿童医院细胞和分子治疗中心，抗盲基金会，Telethon，防盲研究，F M Kirby基金会，Mackall基金会信托，Campania convzione地区，欧盟，意大利眼科协会，科学研究基金，眼科研究基金，国家研究资源中心。
Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber’s congenital amaurosis. We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65-associated Leber’s congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.