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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-大型动物核心