Viral Mediated Gene Therapy for Retinal Diseases

描述(申请人提供)：基因转移的治疗潜力 作为一种治疗视网膜疾病的方法是有希望的，但实质上是技术和 在这项技术能够实现之前，理论问题还有待解决 考虑临床应用。我们研究工作的总体目标是 预防或延缓患者的失明过程。我们的工作重点是 一组遗传性失明疾病称为视网膜色素变性。 目前，还没有被广泛接受的或有效的预防性治疗方法 这一家族的视网膜退化。该项目的目标是测试 神经营养因子对视网膜光感受器的“拯救”能力 退化。来源于腺相关病毒(AAV)和 猫免疫缺陷病毒(FIV)将用于神经营养素的转移 基因进入视网膜。基因转移方法将在几种啮齿动物身上进行评估 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，细胞死亡被归因于几种不同的机制。我们的 潜在的前提是将神经营养因子基因转移到视网膜将 防止细胞死亡，延缓视网膜光感受器和RPE的丢失 退化。在之前的研究中，我们确定了 视网膜中的神经营养因子可以延缓啮齿动物模型的退化 视网膜疾病。在具体目标1中，我们建议优化救援效果 神经营养因子及其组合的载体 可诱导启动子，优化时间表达和剂量。具体而言 目的2，通过提高视网膜基因转移的效率 AAV载体的病毒嗜性修饰及新载体的研制 针对特定类别的视网膜细胞。在具体目标3中，我们将 在这些疾病模型中优化视锥细胞光感受器的存活 神经营养因子的靶向和受控表达。我们将应用 相同的详细解剖和功能(ERG)表征范例 评估在之前的实验中奏效的救援效果。在……里面 总结，此应用程序支持关键的、初始的“原则证明” 创建视网膜特异性病毒载体和系统以转移的实验 视网膜变性基因治疗中的神经营养因子。

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.