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.

项目概要/摘要——大型动物核心 为了实现 CRISPR 视觉计划的目标，确定可接受的剂量至关重要 使用非人类灵长类动物 (NHP) 的候选治疗药物的毒性水平（如果有）。 NHP 眼睛有很多 与常用于研究和药物测试的任何其他物种的眼睛相比，它与人眼的相似性更高。 例如，NHP 是唯一具有黄斑的非人类哺乳动物。在人类中，黄斑很容易受到影响 与许多病理状况有关，例如与年龄相关的黄斑变性，并且通常是 人类视网膜受药物毒性影响最严重。因此，评估包含以下成分的测试物品的效果： NHP 眼睛（尤其是黄斑）的基因组编辑将为安全评估提供大量信息 由 FDA 批准。大型动物核心将提供手术和体内测试专业知识，以确定 拟议的视网膜下给药途径在 NHP 中的适用性和实用性。大型动物核心还将 在测试物品给药期间和之后监测 NHP 的局部（即视网膜下泡附近）的迹象 以及远端视网膜和一般眼部毒性。将监测动物的行为和其他迹象 还有全身毒性。核心将根据以下三项任务进行管理，以支持所有 CRISPR 视觉项目。在任务 1 中，大型动物核心将在视网膜下以 使用经玻璃体方法、小规格玻璃体切除术设备进行手术无菌方式，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 将对动物进行功能和形态学方面的体内眼毒性迹象监测 视网膜下给药。明视和暗视全视野视网膜电图 (ERG) 测试将确定患者的健康状况 整个视网膜。明视多焦点 ERG 将用于评估可能的局部视网膜损伤，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。形态学测定将 包括眼部检查、彩色眼底照片、荧光素血管造影和谱域光学 相干断层扫描。在任务 3 中，大型动物核心将出于目的进行尸检和眼睛检索 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 这些大型动物核心研究将确保对先导治疗进行高效、标准化的评估 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供参考 项目演变。核心负责人 Nork 博士在开发视网膜下方法方面拥有丰富的历史 如果合作伙伴需要的话，注射和眼部评估将提供灵活的方案创新 项目。