Viral Mediated Gene Therapy for Retinal Diseases

描述（由申请人提供）：基因转移的治疗潜力 作为视网膜疾病的治疗是有前途的，但实质性的技术和 在这项技术能够被应用之前， 考虑临床应用。我们研究工作的总体目标是 以预防或延缓患者的失明过程。我们的工作重点是 这是一组遗传性致盲疾病，叫做视网膜色素变性。 目前，没有广泛接受或有效的预防性治疗， 这个视网膜退化家族这个项目的目标是测试 神经营养因子能够“拯救”视网膜光感受器 退化衍生自腺相关病毒（AAV）的病毒载体和 猫免疫缺陷病毒（FIV）将用于转移神经营养因子 基因到视网膜。将在几种啮齿动物中评估基因转移方法 视网膜变性模型（光损伤、RCS、视蛋白突变）。在这些 在啮齿动物模型中，细胞死亡归因于几种不同的机制。我们 潜在的前提是，神经营养因子基因转移到视网膜， 防止细胞死亡，延缓视网膜光感受器和RPE的损失， 退化在以前的研究中，我们确定了 视网膜中的神经营养因子可以减缓啮齿动物模型的变性 视网膜疾病在具体目标1中，我们提出优化救援效果 神经营养因子和因子组合的载体， 诱导型启动子，以优化时间表达和剂量。在特定 目的2，我们将提高视网膜基因转移的效率， 修饰AAV载体的病毒向性和开发新载体 针对特定种类的视网膜细胞。具体目标3： 在这些疾病模型中， 神经营养因子的靶向和受控表达。我们将应用 详细的解剖和功能（ERG）表征的相同范例， 评估在以前的实验中效果良好的救援效果。在 总之，此应用程序支持关键的初始“原理证明” 建立视网膜特异性病毒载体和系统的实验， 神经营养因子用于视网膜变性的基因治疗。

DESCRIPTION (provided by applicant): The therapeutic potential of gene transfer as a treatment for retinal disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be considered for clinical application. The overall goal of our research effort is to prevent or delay the course of blindness in patients. Our work focuses on the group of inherited blinding diseases called Retinitis Pigmentosa. Currently, there is no widely accepted or effective preventive treatment for this family of retinal degenerations. The goal of this project is to test neurotrophic factors for their ability to "rescue" photoreceptors from retinal degeneration. Viral vectors derived from adeno-associated virus (AAV) and feline immunodeficiency virus (FIV) will be used for transfer of neurotrophin genes to the retina. Gene transfer methods will be evaluated in several rodent models of retinal degeneration (light damage, RCS, opsin mutations). In these rodent models, cell death is attributed to several different mechanisms. Our underlying premise is that transfer to the retina of neurotrophin genes will protect against cell death, and delay the photoreceptor and RPE loss in retinal degeneration. In previous studies, we established that expression of Neurotrophic factors in the retina could slow the degeneration in rodent models of retinal disease. In specific aim 1, we propose to optimize the rescue effect of neurotrophic factors and combinations of factors using vectors incorporating inducible promoters to optimize the temporal expression and dose. In specific aim 2, we will increase the efficiency of retinal gene transfer through modifying the viral tropism of the AAV vector and development of new vectors targeted to specific classes of retinal cells. In specific aim 3, we will optimize the survival of cone photoreceptors in these disease models using targeted and controlled expression of neurotrophic factors. We will apply the same paradigm of detailed anatomical and functional (ERG) characterization for evaluating the rescue effect that has worked well in previous experiments. In summary, this application supports key, initial "proof-of-principle" experiments to create retina-specific viral vectors and systems to transfer neurotrophic factors for gene therapy of retinal degeneration.