Large Animal Core

大型动物核心

基本信息

批准号：
10668164
负责人：
T MICHAEL NORK
金额：
$ 20.84万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-16 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668164
关键词：
Acceleration Adverse effects Affect Age related macular degeneration Animals Autopsy Behavior monitoring Bulla Clinical Clustered Regularly Interspaced Short Palindromic Repeats Color Communication Cone Data Distal Dose Drug toxicity Electrophysiology (science)Electroretinography Ensure Equipment Evaluation Evolution Eye Feedback Fluorescein Angiography Formulation Fundus Genome Goals Health Human Individual Industry Inherited Injections Injury Investigational Drugs Laboratories Lead Leber&apos s amaurosis Life Mammals Methods Monitor Morphology Operative Surgical Procedures Optical Coherence Tomography Pathologic Patients Predisposition Primates Principal Investigator Procedures Protocols documentation Recording of previous events Research Research Personnel Retina Retinal Cone Retrieval Route Scanning Services Standardization Sterility Surgeon Techniques Testing Therapeutic Time Toxic effect Toxicity Tests Toxicology Universities Veterinary Medicine Veterinary Schools Vision Visual evoked cortical potential Vitrectomy Wisconsin clinical examination dosage drug distribution drug testing experience fovea centralis fundus imaging genome editing good laboratory practice health assessment in vivo in vivo evaluation industry partner innovation insight macula minimally invasive nonhuman primate pre-clinical programs retinal toxicity safety assessment subretinal injection synergism systemic toxicity therapeutic candidate tissue preparation

项目摘要

PROJECT SUMMARY/ABSTRACT – LARGE ANIMAL CORE To achieve the aims of the CRISPR Vision Program, it will be critically important to determine acceptable dosage and toxicity levels (if any) of therapeutic candidates using nonhuman primates (NHPs). The NHP eye has much greater similarity to the human eye than that of any other species commonly used for research and drug testing. For example, the NHP is the only non-human mammal that has a macula. In humans, the macula is susceptible to a number of pathological conditions such as age-related macular degeneration and is often the part of the human retina most adversely affected by drug toxicity. Hence, evaluating the effects of test articles containing genome editors on the NHP eye, and the macula in particular, will be highly informative for safety assessments by the FDA. The Large Animal Core will provide the surgical and in vivo testing expertise to determine the suitability and practicality of the proposed subretinal dosing route in NHPs. The Large Animal Core will also monitor the NHPs during and after test article dosing for signs of both local (i.e., proximal to the subretinal bleb) and distal retinal and general ocular toxicity. The animals will be monitored for behavior and other indications of systemic toxicity, as well. The Core will be administered under the following three Tasks to support all of the CRISPR Vision Projects. In Task 1, the Large Animal Core will administer the test article subretinally in a surgically sterile manner using a trans-vitreous approach, small-gauge pars plana vitrectomy equipment, and automated subretinal injector. In Task 2, the Large Animal Core will perform in vivo toxicity evaluations. The animals will be monitored both functionally and morphologically for in vivo signs of ocular toxicity following subretinal dosing. Photopic and scotopic full-field electroretinography (ERG) testing will determine the health of the entire retina. Photopic multifocal ERG will be used to assess possible localized retinal injury, either from the subretinal injection procedure itself or localized toxicity of the test article. Morphological determinations will include ocular examinations, color fundus photographs, fluorescein angiography and spectral domain optical coherence tomography. In Task 3, the Large Animal Core will perform necropsy and eye retrieval for purposes of determining drug distribution and histopathological signs of drug toxicity. The expertise and centralization of these studies in the Large Animal Core will ensure efficient, standardized assessment of lead therapeutic products nominated by all three CRISPR Vision Program Projects, with near real-time data return to inform Project evolution. The extensive history of the Core Lead, Dr. Nork, with developing methods for subretinal injection and ocular evaluations will provide nimble protocol innovation if required over the span of the partner Projects.

项目摘要/摘要 - 大动物核心为了实现CRISPR愿景计划的目标，确定可接受的剂量至关重要使用非人类素数（NHP）的理论候选者和毒性水平（如果有）。 NHP眼有很多与人眼的相似性要比任何其他用于研究和药物测试的其他物种的相似性。例如，NHP是唯一具有黄斑的非人类哺乳动物。在人类中，黄斑易感对于许多病理状况，例如与年龄相关的黄斑变性，通常是人类视网膜受到药物毒性的影响最大。因此，评估包含测试文章的影响 NHP眼中的基因组编辑者，尤其是黄斑，对于安全评估，将为安全评估提供高度信息由FDA。大动物核心将提供手术和体内测试专业知识，以确定 NHPS拟议的视网膜下给药路线的适用性和实用性。大动物核心也将在测试文章剂量期间和之后监视NHP的局部迹象（即，接近视网膜下BLEB）以及独特的视网膜和一般眼毒性。将监视动物的行为和其他指示系统性毒性也是如此。核心将在以下三个任务下进行管理，以支持所有 CRISPR视觉项目。在任务1中，大动物核心将在A下续下测试文章使用反视力方法，小规模pars planta玻璃体切除术设备和自动下注射器。在任务2中，大动物核心将进行体内毒性评估。这将在功能和形态上监测动物，以了解眼部毒性的体内迹象视网膜下给药。光波和SCOTOPIC全场电视图（ERG）测试将确定整个视网膜。光波多灶性ERG将用于评估可能的局部视网膜损伤，要么是从视网膜下注射程序本身或测试条款的局部毒性。形态学决定将包括眼检查，颜色眼睛照片，荧光素血管造影和光谱域光学相干断层扫描。在任务3中，大动物核心将进行尸检和目的的眼睛检索确定药物分布和药物毒性的组织病理学迹象。专业知识和集中化这些在大动物核心中的研究将确保对铅治疗的有效，标准化评估由所有三个CRISPR视觉计划项目提名的产品，近乎实时的数据返回以告知项目演变。核心铅的广泛历史Nork博士，开发了视网膜下的方法如果需要，注射和眼评估将提供敏捷的协议创新项目。