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.

项目总结/摘要-大型动物核心 为了实现CRISPR愿景计划的目标，确定可接受的剂量至关重要。 以及使用非人灵长类动物（NHP）的治疗候选物的毒性水平（如果有的话）。NHP的眼睛有很多 与人眼的相似性比任何其他常用于研究和药物测试的物种都要大。 例如，NHP是唯一具有黄斑的非人类哺乳动物。人类的黄斑 许多病理状况，如年龄相关性黄斑变性，往往是部分的 人类视网膜最受药物毒性的不利影响。因此，评价含有以下物质的供试品的影响 NHP眼睛上的基因组编辑器，特别是黄斑，将为安全性评估提供高度信息 被FDA。大型动物中心将提供手术和体内试验专业知识，以确定 建议的视网膜下给药途径在NHP中的适用性和实用性。大型动物中心还将 在供试品给药期间和之后监测NHP的局部（即，视网膜下泡近端） 以及远端视网膜和全身眼部毒性。将监测动物的行为和其他迹象， 还有全身毒性核心方案将根据以下三项任务进行管理， CRISPR Vision Projects.在任务1中，大型动物中心将在视网膜下给予供试品， 采用经玻璃体入路、小规格玻璃体切除术设备的无菌手术方式，以及 自动视网膜下注射器在任务2中，大型动物中心将进行体内毒性评价。的 将在功能上和形态学上监测动物的眼毒性体内体征， 视网膜下给药。明视和暗视全视野视网膜电图（ERG）测试将确定健康的 整个视网膜。明视多焦ERG将用于评估可能的局部视网膜损伤， 视网膜下注射程序本身或供试品的局部毒性。形态测定将 包括眼部检查、彩色眼底照片、荧光素血管造影和光谱域光学 相干断层扫描在任务3中，大型动物中心将进行尸检和取眼， 确定药物分布和药物毒性的组织病理学体征。专业知识和集中化 这些大型动物中心的研究将确保对铅治疗的有效、标准化评估， 所有三个CRISPR Vision Program项目提名的产品，近实时数据返回， 项目进展。核心负责人Nork博士开发视网膜下治疗方法的广泛历史 注射和眼部评估将提供灵活的方案创新，如果需要在合作伙伴的跨度 项目