Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, and Center for Cellelar and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sci Transl Med. 2011 Jun 22;3(88):88ra54. doi: 10.1126/scitranslmed.3002103.
Gene therapy is emerging as a therapeutic modality for treating disorders of the retina. Photoreceptor cells are the primary cell type affected in many inherited diseases of retinal degeneration. Successfully treating these diseases with gene therapy requires the identification of efficient and safe targeting vectors that can transduce photoreceptor cells. One serotype of adeno-associated virus, AAV2, has been used successfully in clinical trials to treat a form of congenital blindness that requires transduction of the supporting cells of the retina in the retinal pigment epithelium (RPE). Here, we determined the dose required to achieve targeting of AAV2 and AAV8 vectors to photoreceptors in nonhuman primates. Transgene expression in animals injected subretinally with various doses of AAV2 or AAV8 vectors carrying a green fluorescent protein transgene was correlated with surgical, clinical, and immunological observations. Both AAV2 and AAV8 demonstrated efficient transduction of RPE, but AAV8 was markedly better at targeting photoreceptor cells. These preclinical results provide guidance for optimal vector and dose selection in future human gene therapy trials to treat retinal diseases caused by loss of photoreceptors.
基因治疗正在成为治疗视网膜疾病的一种治疗方法。光感受器细胞是许多遗传性视网膜变性疾病中受影响的主要细胞类型。成功地用基因治疗治疗这些疾病需要鉴定能够转导光感受器细胞的有效和安全的靶向载体。一种腺相关病毒血清型 AAV2 已成功用于临床试验，以治疗需要转导视网膜色素上皮（RPE）中视网膜支持细胞的一种先天性失明形式。在这里，我们确定了达到非人类灵长类动物光感受器靶向所需的 AAV2 和 AAV8 载体的剂量。用携带绿色荧光蛋白转基因的各种剂量的 AAV2 或 AAV8 载体进行眼内下注射的动物中转基因表达与手术、临床和免疫学观察相关。AAV2 和 AAV8 均显示出对 RPE 的有效转导，但 AAV8 对光感受器细胞的靶向作用明显更好。这些临床前结果为未来治疗由光感受器丧失引起的视网膜疾病的人类基因治疗试验中的最佳载体和剂量选择提供了指导。
