Defining Barriers to Gene Therapy

定义基因治疗的障碍

基本信息

批准号：
9301555
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/9301555
关键词：
Address Affect Age related macular degeneration Age-Years American Animal Model Atrophic Bilateral 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 Follow-Up Studies Funding Fundus Future Gene Transfer Gene therapy trial 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 Pathologic Patients Pattern Peripheral Pharmacology Phase Phenotype Photoreceptors Pre-Clinical Model Reporting Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Safety Secondary to Series Study models System Testing Therapeutic Therapeutic Intervention Therapy trial Time Toxic effect Trauma Treatment Efficacy Treatment Failure Universities Validation Vertebrate Photoreceptors Viral Genes Vision Visual Acuity Visual Fields Work clinically relevant cohort combinatorial complement C2a cone-rod degeneration end stage disease gene therapy imaging biomarker 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和与年龄相关的黄斑变性（AMD）中，棒感受器的进行性萎缩会导致锥形感受器的继发性死亡。基因治疗是增强或恢复杆生存力的潜在手段，从而防止次级锥体损失。然而，第一个针对RP的人类基因疗法试验发现了视觉功能的提高，但没有减慢感光体的变性。该基因治疗的目标的目的是确定在已经患病的视网膜的背景下是否可以实现治疗。由CGMP磷酸二酯酶6（PDE6）缺乏引起的RP是研究杆的进行性细胞自主性变性以及随后的非细胞自主锥体损失的理想模型。在上一个资金期间，我们通过在变性开始前使用病毒基因转移方法在PDE6缺陷的小鼠中成功恢复了PDE6活性和视网膜功能超过11个月。现在，在AIM 1中，我们建议确定小鼠棒和锥体是否可以在临床相关的时间窗口中救出 - 也就是说，通常在诊断出患者时变性后。为此，我们生成了一种新型的诱导遗传救援系统，使我们能够有条件地逆转PDE6缺陷，并控制表型反转的数值，时间和空间方面。我们将使用这种非外科和健壮的基因治疗方法来确定视力恢复/保存是否受杆救援的时间（AIM 1A）的影响（AIM 1A），被救出的杆数量（AIM 1A）以及突变杆的非自治作用（AIM 1B）。为了补充RP的研究及其在动物模型中的救助，我们在上一个资金期间在小鼠中开发了一种非侵入性自动荧光成像技术。由于FDA尚未接受成像生物标志物作为视网膜疾病治疗疗效的主要结果指标，因此我们将研究非侵入性成像是否可以替代评估小鼠和人类的疾病进展（AIM 2）。如果没有新的疾病预测因素来替代不太敏感的常规测试，确定治疗方法的适当性和/或建立以评估功效（疾病进展或稳定）的基线是具有挑战性的。新型的非侵入性成像生物标志物将使我们能够告知RP患者疾病的预后和治疗选择。此外，他们将解决迫切建议，以建议已经有一个被诊断为RP的孩子的新准父母提供建议。综上所述，该提议可以肯定地1）定义限制介入疗法的因素； 2）验证一个新的工具套件，以控制欧洲有条件小鼠诱变程序队列中任何基因的光感受器特异性表达的药理控制； 3）确定疾病进展的新型成像生物标志物对于评估第2阶段和3次临床试验的功效至关重要，4）有助于当前和未来的基本机械人类和动物模型中光感受器变性的研究。