Defining Barriers to Gene Therapy

定义基因治疗的障碍

基本信息

批准号：
8703280
负责人：
Stephen H Tsang
金额：
$ 40万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703280
关键词：
Address Affect Age related macular degeneration Age-Years American Animal Model Atrophic Bilateral Biological Markers Biological Preservation Blindness Cell Death Cell Therapy Cells Cessation of life Child Clinical Trials Complement Cone Contralateral Cyclic GMP Data Set Databases Death Rate Defect Diagnosis Diagnostic Disease Disease Progression Dysmorphology Electroretinography Enrollment European Exhibits Eye Failure Funding Fundus Future Gene Transfer Genes Genetic Genotype Goals Human Image Imaging Techniques Inherited Laboratories LacZ Genes Light Measurement Measures Mediating Methods Monitor Mus Mutagenesis Onset of illness Optical Coherence Tomography Outcome Outcome Measure Parents Patients Pattern Peripheral Phase Photoreceptors Pre-Clinical Model Relative (related person)Reporting Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Safety Secondary to Series Study models System Testing Therapeutic Time Toxic effect Trauma Treatment Efficacy Treatment Failure Universities Validation Vertebrate Photoreceptors Viral Genes Vision Visual Acuity Visual Fields Work clinically relevant cohort combinatorial cone-rod degeneration end stage disease follow-up gene therapy imaging modality improved internal control killings mouse model mutant non-invasive imaging novel outcome forecast phosphodiesterase 6 phosphoric diester hydrolase photoreceptor degeneration pre-clinical prevent primary outcome programs public health relevance restoration retinal rods subretinal injection therapeutic gene tool vector

项目摘要

DESCRIPTION (provided by applicant): Of the retinal degenerative diseases that affect 9 million Americans, retinitis pigmentosa (RP) is the most devastating. In RP and age-related macular degeneration (AMD), progressive atrophy of rod photoreceptors leads to secondary death of cone photoreceptors. Gene therapy is a potential means to strengthen or restore rod viability, thereby preventing secondary cone loss. However, the first human gene-therapy trial for RP 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. RP resulting from cGMP phosphodiesterase-6 (PDE6) deficiency is an ideal model for studying progressive cell- autonomous degeneration of rods and subsequent, non-cell-autonomous cone loss. During the previous funding period, we succeeded in restoring PDE6 activity and retinal function for more than 11 months in PDE6- deficient mice by using viral gene transfer methods before the onset of degeneration. We now propose, in Aim 1, to determine whether mouse rods and cones can be rescued within a clinically relevant time window - that is, after the onset of degeneration when patients are usually diagnosed. To do this, we generate a novel inducible genetic rescue system that allows us to conditionally reverse PDE6-deficiency and to control numerical, temporal and spatial aspects of phenotypic reversal. We will use this nonsurgical and robust gene therapy approach to determine if vision restoration/preservation is influenced by the timing of rod rescue (Aim 1a), the number of rods rescued (Aim 1a), and non-autonomous effects of mutant rods (Aim 1b). To complement the study of RP and its rescue in animal models, we have developed a non-invasive autofluorescence imaging technique in mice during the previous funding period. Because FDA is yet to accept imaging biomarkers as a primary outcome measure for treatment efficacy for retinal diseases, we will investigate whether non-invasive imaging can be a surrogate to assess disease progression in both mice and humans (Aim 2). Without novel disease predictors to replace conventional tests that are not deemed not sensitive enough, it is challenging to determine the appropriateness of a therapeutic approach, and/or to establish a baseline from which to assess efficacy (disease progression or stabilization). The novel non-invasive imaging biomarkers will enable us to inform RP patients their disease prognosis and treatment options. Furthermore, they will address the urgency to advise newly expectant parents who already have one child diagnosed with RP. Taken together, this proposal is certain to 1) define the factors limiting interventional therapy; 2) validate a new tool kit for pharmacological control of photoreceptor-specific expression of any gene in the European Conditional Mouse Mutagenesis Program cohort; 3) identify novel imaging biomarkers of disease progression essential for assessing efficacy in phase 2 and 3 clinical trials and 4) aid current and future basic mechanistic studies of photoreceptor degeneration in humans and animal models.

描述（由申请人提供）：在影响 900 万美国人的视网膜退行性疾病中，色素性视网膜炎 (RP) 是最具破坏性的。在 RP 和年龄相关性黄斑变性 (AMD) 中，视杆细胞感光细胞进行性萎缩导致视锥细胞感光细胞继发性死亡。基因治疗是增强或恢复视杆细胞活力的潜在方法，从而防止继发性视锥细胞损失。然而，第一个针对 RP 的人类基因治疗试验发现视觉功能有所改善，但并没有减缓光感受器的退化。这项以基因治疗为导向的提案的目标是确定在已经患病的视网膜的情况下是否可以实现治疗。由 cGMP 磷酸二酯酶 6 (PDE6) 缺陷引起的 RP 是研究进行性细胞自主性视杆细胞退化和随后的非细胞自主性视锥细胞丧失的理想模型。在之前的资助期间，我们通过使用病毒基因转移方法，在PDE6缺陷小鼠变性发生之前成功恢复了PDE6活性和视网膜功能超过11个月。现在，我们在目标 1 中提出，确定是否可以在临床相关的时间窗口内（即在患者通常被诊断出变性发生之后）来挽救小鼠的视杆细胞和视锥细胞。为此，我们生成了一种新型诱导型基因拯救系统，使我们能够有条件地逆转 PDE6 缺陷并控制表型逆转的数字、时间和空间方面。我们将使用这种非手术且强大的基因治疗方法来确定视力恢复/保留是否受到视杆细胞救援时间（目标 1a）、救援视杆细胞数量（目标 1a）和突变视杆细胞的非自主效应（目标 1a）的影响。 1b).为了补充 RP 及其在动物模型中的拯救研究，我们在上一个资助期间开发了一种小鼠非侵入性自发荧光成像技术。由于 FDA 尚未接受成像生物标志物作为视网膜疾病治疗效果的主要结果指标，因此我们将研究非侵入性成像是否可以作为评估小鼠和人类疾病进展的替代方法（目标 2）。如果没有新的疾病预测因子来取代被认为不够敏感的传统测试，那么确定治疗方法的适当性和/或建立评估疗效（疾病进展或稳定）的基线就具有挑战性。新型非侵入性成像生物标志物将使我们能够告知 RP 患者的疾病预后和治疗选择。此外，他们还将解决向已经有一个孩子被诊断患有 RP 的新准父母提供建议的紧迫性。综上所述，该建议肯定会：1）明确限制介入治疗的因素； 2) 验证一个新的工具包，用于对欧洲条件小鼠诱变计划队列中任何基因的光感受器特异性表达进行药理学控制； 3) 识别疾病进展的新型影像生物标志物，对于评估 2 期和 3 期临床试验的疗效至关重要，4) 帮助当前和未来的基本机制人类和动物模型中光感受器变性的研究。