RPE65基因疗法治疗莱伯先天性黑蒙的年龄依赖性效应：一项1期剂量递增试验。
Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.
作者信息
Maguire Albert M, High Katherine A, Auricchio Alberto, Wright J Fraser, Pierce Eric A, Testa Francesco, Mingozzi Federico, Bennicelli Jeannette L, Ying Gui-shuang, Rossi Settimio, Fulton Ann, Marshall Kathleen A, Banfi Sandro, 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
机构信息
F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
出版信息
Lancet. 2009 Nov 7;374(9701):1597-605. doi: 10.1016/S0140-6736(09)61836-5. Epub 2009 Oct 23.
BACKGROUND
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.
METHODS
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 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years.
FINDINGS
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.
INTERPRETATION
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.
FUNDING
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.
背景
基因疗法有潜力逆转疾病或防止患有无法治愈的遗传性视网膜变性的患者视力进一步恶化。因此，我们开展了一项1期试验，以评估基因疗法对患有莱伯先天性黑蒙的儿童和成人视网膜及视觉功能的影响。
方法
我们评估了12例年龄在8至44岁、患有与RPE65相关的莱伯先天性黑蒙的患者的视网膜和视觉功能。在其最差的一只眼中，给予一次视网膜下注射含编码视网膜色素上皮异构水解酶活性所需蛋白质的基因的腺相关病毒（AAV）（AAV2-hRPE65v2），剂量分别为低剂量（1.5×10¹⁰载体基因组）、中剂量（4.8×10¹⁰载体基因组）或高剂量（1.5×10¹¹载体基因组），随访长达2年。
结果
AAV2-hRPE65v2耐受性良好，所有患者在视力的主观和客观测量指标（即暗适应测量、瞳孔测量、视网膜电图、眼球震颤和行走行为）上均显示出持续改善。患者的瞳孔光反应至少增加了2个对数单位，一名8岁儿童的光敏感度与年龄匹配的正常视力个体几乎相同。儿童的改善最为显著，所有儿童均获得了可自主行走的视力。该研究已在ClinicalTrials.gov注册，编号为NCT00516477。
解读
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。
资助
费城儿童医院细胞与分子治疗中心、抗击失明基金会、Telethon、预防失明研究组织、F M Kirby基金会、Mackall基金会信托、坎帕尼亚大区协议、欧盟、意大利莱伯先天性黑蒙协会、科学研究基金、眼科研究基金和国家研究资源中心。
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