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Disease modeling and CRISPR/Cas9-mediated rescue of dominant Leber congenital amaurosis retinal phenotypes

疾病建模和 CRISPR/Cas9 介导的显性 Leber 先天性黑蒙视网膜表型的挽救

基本信息

批准号：
10397068
负责人：
Kathleen R Chirco
金额：
$ 4.28万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397068
关键词：
Affect Alleles Animals Binding Binding Sites Biochemical Biological Models Blindness CRISPR therapeutics CRISPR/Cas technology CRX protein Cell Maturation Cell physiology Child Clinic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collaborations DNA Binding Development Disease Disease model Dominant-Negative Mutation Excision Foundations Functional disorder Future Genes Genetic Transcription Goals Histologic Human In Vitro Individual Inherited Investigation K-Series Research Career Programs Knock-out Laboratories Lead Leber&apos s amaurosis Mediating Methods Modeling Mus Mutation Newborn Infant Organoids Patients Phenotype Photoreceptors Protocols documentation Publishing Retina Retinal Degeneration Retinal Diseases Retinal Dystrophy School-Age Population Solid System Techniques Testing Therapeutic Therapeutic Studies Translational Research Variant Vision research Visual Acuity Work alternative treatment base developmental disease disease phenotype early onset effective therapy experience functional restoration gene correction gene replacement gene therapy improved in vitro Model in vivo induced pluripotent stem cell insight mouse model mutant novel strategies novel therapeutic intervention post-doctoral training protein function protein protein interaction sight restoration stem cells therapeutic development therapeutic gene tool treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Leber congenital amaurosis (LCA) is a group of devastating early-onset retinal dystrophies affecting roughly 1/50,000 to 1/33,000 newborns. LCA-associated variants in the CRX gene result in a severe autosomal dominant form of the disease, for which no effective treatments are currently available. Therefore, despite substantial progress being made in the field, there is a critical need to uncover pathophysiology and establish reliable treatment options for CRX-associated LCA. The overall goal of this proposal is to bring together two major unsolved problems in vision research: (1) the ability to accurately recapitulate dominant LCA in a scalable in vitro model system to study variant-specific disease mechanisms, and (2) the ability to efficiently and specifically eliminate dominant disease alleles, leaving healthy alleles to restore photoreceptor cell function. In Aim 1, variant-specific disease mechanisms responsible for the onset of LCA will be examined by generating a retinal organoid model system from patient-derived induced pluripotent stem cells. These studies will establish a model system for mechanistic characterization of LCA and will provide insight into alternative treatment strategies for this disease. In Aim 2, mutant CRX alleles will be inactivated with CRISPR tools within the human retinal organoid model to study rescue of disease phenotypes. Importantly, both mouse and human studies suggest that haploinsufficiency is not responsible for disease manifestation in dominant CRX-associated LCA, and one copy of wildtype CRX is enough to allow for mostly normal photoreceptor maturation and function. Completion of this aim will provide the field with a proof-of-concept study for the development of patient-specific CRISPR-based therapeutic strategies. Taken together, the proposed studies will contribute to our basic understanding of the pathophysiological mechanisms underlying photoreceptor dysfunction in dominant CRX-associated LCA, and will enable the development of targeted gene therapies to treat affected individuals.

项目总结/文摘