Large Animal Core

大型动物核心

• 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
• 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' 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

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-大型动物核心 为了实现CRISPR Vision Program的目标，确定可接受的剂量至关重要 以及使用非人类灵长类动物(HHP)的治疗候选者的毒性水平(如果有的话)。NHP的眼睛有很多 与通常用于研究和药物测试的任何其他物种相比，它与人眼的相似性更大。 例如，NHP是唯一一种有黄斑的非人类哺乳动物。在人类中，黄斑是敏感的。 一些病理情况，如年龄相关性黄斑变性，通常是 人类的视网膜最容易受到药物毒性的影响。因此，评估包含以下内容的测试品的效果 NHP眼睛上的基因组编辑，特别是黄斑，将为安全评估提供大量信息 被美国食品和药物管理局。大型动物核心中心将提供外科和活体测试专业知识，以确定 建议的视网膜下给药途径在NHPS中的适用性和实用性。大型动物核心也将 在给药期间和给药后监测NHP，看是否有局部(即视网膜下小泡近端)的迹象 以及远端视网膜和全身眼部毒性。这些动物的行为和其他迹象将被监测 全身毒性也是如此。核心将根据以下三项任务进行管理，以支持所有 CRISPR愿景项目。在任务1中，大动物核心将在视网膜下管理测试文章 使用经玻璃体入路、小口径平坦部玻璃体切割术的无菌手术方式，以及 自动视网膜下注射器。在任务2中，大型动物核心将进行体内毒性评估。这个 将对动物进行功能和形态上的监测，以确定下列动物的眼部毒性迹象 视网膜下给药。照片和暗视全场视网膜电图(ERG)测试将决定患者的健康 整个视网膜。将使用照片多焦点ERG来评估可能的局限性视网膜损伤，无论是来自 视网膜下注射程序本身或测试物品的局部毒性。形态测定将 包括眼科检查、彩色眼底照片、荧光素血管造影术和光谱域光学 相干层析成像。在任务3中，大型动物核心将进行尸检和取回眼睛的目的 确定药物分布和药物毒性的组织病理学迹象。的专业知识和集中化 这些大型动物核心研究将确保对铅治疗进行有效、标准化的评估 所有三个CRISPR愿景计划项目提名的产品，具有近乎实时的数据返回通知 项目演进。Core Lead的广泛历史，Nork博士，开发视网膜下的方法 如果合作伙伴需要，注射和目测评估将提供灵活的协议创新 项目。