Viral Mediated Gene Therapy for Retinal Diseases

病毒介导的视网膜疾病基因治疗

• 批准号: 6751520
• 负责人: John Gerard Flannery
• 金额: $ 36.67万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751520
• 关键词: Adenoviridae; apoptosis; biotechnology; cell type; cone cell; feline immunodeficiency virus; gene delivery system; gene therapy; genetic manipulation; genetic transcription; laboratory rat; neurotrophic factors; nonhuman therapy evaluation; retina degeneration; retinitis pigmentosa; rod cell; technology /technique development; transfection /expression vector; virus receptors; visual photoreceptor

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.

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希望的，但技术的实质性和 在这项技术可以解决之前，理论问题仍有待解决 考虑用于临床应用。我们研究工作的总体目标是 防止或延迟患者失明的过程。我们的工作专注于 一组称为视网膜炎色素炎的遗传性盲疾病。 目前，尚无广泛接受或有效的预防治疗 这个视网膜变性家族。该项目的目的是测试 神经营养因素的能力从视网膜中“拯救”感光器 退化。源自腺相关病毒（AAV）的病毒载体和 猫免疫缺陷病毒（FIV）将用于神经营养素的转移 视网膜的基因。基因转移方法将在几种啮齿动物中评估 视网膜变性模型（轻损伤，RCS，Opsin突变）。在这些 啮齿动物模型，细胞死亡归因于几种不同的机制。我们的 基本的前提是转移到神经营养蛋白基因的视网膜将 防止细胞死亡，并延迟视网膜的光感受器和RPE损失 退化。在先前的研究中，我们确定了 视网膜中的神经营养因子可以减慢啮齿动物模型的变性 视网膜疾病。在特定目标1中，我们建议优化救援效果 神经营养因素和使用载体合并的因子的组合 诱导启动子以优化时间表达和剂量。具体 AIM 2，我们将提高视网膜基因转移的效率 修改AAV载体的病毒向向主义和新向量的发展 针对特定类别的视网膜细胞。在特定的目标3中，我们将 使用这些疾病模型中锥形感受器的存活 靶向和控制神经营养因子的表达。我们将应用 相同的详细解剖学和功能（ERG）表征的范式 评估在先前实验中效果很好的救援效应。在 摘要，此应用程序支持关键，初始“原理证明” 实验创建视网膜特异性病毒向量和系统以转移 视网膜变性基因治疗的神经营养因子。