Defining Barriers to Gene Therapy

定义基因治疗的障碍

基本信息

批准号：
10163849
负责人：
Stephen H Tsang
金额：
$ 34.69万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163849
关键词：
Ablation Address Adult Affect Age Age-Years Alleles American Anabolism Binding Catabolism Cessation of life Clinical Trials Combined Modality Therapy Cone Cone dystrophy Cre driver Data Degenerative Disorder Diagnosis Disease Electroretinography Engineering European Functional disorder Funding GTP-Binding Proteins Gene therapy trial Genes Genetic Genotype Glycolysis Goals Grant Guanine Nucleotides Human Injections Intervention Light LoxP-flanked allele Measurement Mediating Metabolic Methods Modeling Mus Mutagenesis Mutation Onset of illness Outcome Pathologic Pathway interactions Patients Peer Review Phase Phenotype Photoreceptors Public Health Publications Quality of life Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal Dystrophy Risk Rod Sirtuins Study models Supplementation System Tamoxifen Testing Therapeutic Therapeutic Intervention Time Transcription Repressor Vertebrate Photoreceptors Viral Vector Vision alpha Subunit Transducin base brain circuitry clinically relevant cost efficient design effectiveness evaluation efficacious treatment experience experimental study gene function gene therapy human model improved innovation meetings metabolome mouse model novel phosphoric diester hydrolase photoreceptor degeneration programs restoration small molecule tool

项目摘要

PROJECT SUMMARY Of the retinal degenerative diseases that affect 9 million Americans, cone photoreceptor dystrophies are arguably the most devastating. Gene therapy is a potential means to strengthen photoreceptor viability. However, the first human gene therapy trial for retinal degeneration found improved visual function but did not slow degeneration of photoreceptors. The goal of this gene therapy-oriented proposal is to determine whether therapy is achievable in the context of an already diseased retina and if metabolic reprogramming could be an efficacious treatment option. During the previous funding period, we succeeded in restoring retinal function for more than 11 months in a mouse model of rod degeneration even after the onset of degeneration and at late-stage disease. We now intend to determine whether the same outcomes are achievable in cone-based dystrophies. To do this, we will generate a novel, inducible genetic rescue system in the cone-specific G-protein, guanine nucleotide binding α- transducin 2 (Gnat2), which will allow us to conditionally reverse GNAT2-deficiency while controlling the temporal and spatial aspects of phenotypic reversal. Using Gnat2floxSTOP/Gnat2CreERT2, we will establish that the model faithfully recapitulates cone-mediated dystrophies (Aim 1). We will restore the model to wild type via tamoxifen injection at early, middle, and late disease stages and assess effects on the rate of degeneration (Aim 2) to determine the temporal limitations of gene therapy. Finally, we will induce metabolic reprogramming and assess its utility as a possible non-gene- specific strategy for treating cone degenerations -based dystrophies (Aim 3). The Gnat2floxSTOP/Gnat2CreERT2 programmable model will provide a platform for contributing to ongoing efforts aimed at increasing restoration of visual function following gene therapy for cone-mediated dystrophies. It will also allow us to address several compelling, clinically relevant questions: Is the brain’s circuitry sufficiently plastic to recover from the pathological changes caused by the Gnat2 mutation? Is there a point of no return after which, despite reversion of the genotype to wild type, cones cannot be salvaged? Can temporal barriers to gene therapy be relieved by metabolic reprogramming? Taken together, this proposal is certain to 1) define the factors limiting interventional therapy; 2) validate a new, inducible model of cone-mediated retinal degeneration; and 3) determine whether metabolic reprogramming can serve as an efficacious, non-gene-specific strategy for treating retinal degeneration.

项目概要在影响 900 万美国人的视网膜退行性疾病中，视锥细胞营养不良最具争议的是基因治疗是增强光感受器活力的潜在手段。然而，第一个针对视网膜变性的人类基因治疗试验发现视觉功能有所改善，但并没有这项以基因治疗为导向的提案的目标是确定是否会导致光感受器的缓慢退化。在已经患病的视网膜的情况下，如果代谢重编程可以成为一种治疗方法，那么治疗是可以实现的。有效的治疗选择。在上一个资助期间，我们成功恢复了视网膜功能超过11个月在小鼠视杆细胞退化模型中，即使在退化发生后和疾病晚期，我们也发现了这一点。打算确定在视锥细胞营养不良中是否可以实现相同的结果。在锥体特异性 G 蛋白、鸟嘌呤核苷酸结合 α- 中产生新型诱导型遗传拯救系统 transducin 2 (Gnat2)，这将使我们能够有条件地逆转 GNAT2 缺陷，同时控制时间和表型逆转的空间方面。使用 Gnat2floxSTOP/Gnat2CreERT2，我们将建立该模型忠实地再现视锥介导的我们将通过早期、中期和晚期注射他莫昔芬将模型恢复为野生型。疾病阶段并评估对退化率的影响（目标 2）以确定疾病的时间限制最后，我们将诱导代谢重编程并评估其作为一种可能的非基因疗法的效用。治疗基于锥体变性的营养不良的具体策略（目标 3）。 Gnat2floxSTOP/Gnat2CreERT2 可编程模型将为持续进行的贡献提供一个平台旨在加强视锥细胞介导的营养不良基因治疗后视觉功能的恢复。它还将使我们能够解决几个引人注目的、临床相关的问题：大脑的电路是否具有足够的可塑性以从 Gnat2 突变引起的病理变化中恢复吗？没有返回，尽管基因型恢复为野生型，但视锥细胞无法挽救？代谢重编程可以消除基因治疗的障碍吗？综上所述，该建议肯定会 1) 定义限制介入治疗的因素；2) 验证视锥细胞介导的视网膜变性的新诱导模型；3) 确定是否存在代谢重编程；可以作为治疗视网膜变性的有效的、非基因特异性的策略。