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CRISPR Editing of Primary Human Cells to Model and Correct Primary Immunodeficiency Mutations

对原代人类细胞进行 CRISPR 编辑以建模和纠正原发性免疫缺陷突变

基本信息

批准号：
10203787
负责人：
David-Huy Nhu Nguyen
金额：
$ 19.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10203787
关键词：
Address Affect Alleles Animal Model Autologous Basic Science Benign Biology CRISPR/Cas technology CTLA4 gene Catalogs Cell Death Cell Line Cell Therapy Cell Transplantation Cells Cellular biology Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Complement Complementary DNA Counseling DNA DNA Modification Process DNA Repair DNA Structure Databases Development Diagnosis Diagnostic Disease Doctor of Philosophy Dose Drug Delivery Systems Engineering Environment Faculty Funding Gene Expression Genes Genetic Genetic Code Genetic Diseases Genetic Screening Genome engineering Genomics Goals Hematopoietic stem cells Heterozygote Homo Human Hybrids IL2RA gene IL2RG gene Immune Immune System Diseases Immune response Immune system Immunologic Deficiency Syndromes Immunology Individual Infection Instruction JAK3 gene Knock-in Knowledge Lead Learning Libraries Link Maps Medical Mentors Methods Modeling Molecular Diagnosis Mutate Mutation Mutation Analysis Outcome Pathologic Pathology Patients Physicians Population Prognosis Proteins Reporter Reporter Genes Research Research Personnel Research Training Scientist Severe Combined Immunodeficiency Signal Transduction Site Surface System T-Lymphocyte TNFSF5 gene Techniques Technology Testing Toxic effect Training Transformed Cell Line Translational Research Variant Work base career career development causal variant cell bank cell growth cell type clinical care clinical sequencing clinically significant congenital immunodeficiency cytotoxic diagnostic platform disease diagnosis disease-causing mutation exome sequencing fighting functional genomics functional outcomes gene correction gene therapy genetic variant immune function improved innovation large datasets lectures member mutation correction mutation screening next generation sequencing novel novel diagnostics novel strategies novel therapeutics nuclease pre-clinical preclinical development prototype receptor response skills small molecule therapeutic genome editing tool transplantation therapy

项目摘要

PROJECT SUMMARY / ABSTRACT The goal of this application is to train Dr. David Nguyen PhD MD, an infectious disease clinician and medical engineer, with the skills necessary to become an independently-funded investigator studying, diagnosing, and eventually curing genetic diseases of the immune system. Primary immunodeficiency (PID) disease is commonly recognized as an inability of the immune system to develop, self-regulate, or fight infection due to a genetic defect in some aspect of the normal immune response. Gene therapy is a possibility to cure PID disease once a patient's mutation can be identified, but there is incomplete knowledge of the genetic underpinnings of PID. PID-causative mutations often remain undiagnosed despite state-of-the-art genomic sequencing efforts because of an inability to separate benign sequence variations from the truly pathologic mutations. This research plan addresses key limitations in the ability to provide a molecular diagnosis and cure for PID patients. Dr. Nguyen will utilize recently developed advanced CRISPR-gene editing tools in innovative ways to study PID-associated mutations and understand how they lead to clinical disease. He will then develop novel strategies for replacing PID mutations in a patient's own hematopoietic stem progenitor cells (HSPCs). He aims to 1) accurately recreate and functionally test PID patient sequencing variants by replacing wild-type alleles in (otherwise healthy) primary human immune cells, 2) utilize high-throughput functional genomics to catalogue all possible mutations in key PID-associated genes that could lead to immune dysfunction, 3) improve site- specific gene correction in primary HSPCS. The proposed a 5-year career development and training plan incorporates didactic lecture-based learning, mentored practical training, and career advising to complement Dr. Nguyen's expertise in ways that are critical to completion of his research and career goals. He will receive instruction in advanced human T cell and HSPC biology, functional genomics methods in particular next-generation sequencing techniques and manipulation of large datasets, and pre-clinical development of cell and gene therapies. He will be training at UCSF, a center for both basic and translational research that provides an excellent environment supporting physician-scientists with local experts in all aspects the proposed research and training goals. He will be closely mentored by Dr. Alexander Marson, a leading expert in using CRISPR gene editing to understand the genetic basis of human immune function, and Dr. Jennifer Puck, a world-leader in the diagnostics, genetics, clinical care, and gene therapy of severe combined immunodeficiency. The long-term goal of this study is to provide Dr. Nguyen with the skills required to become a R01-funded faculty member leading efforts to identify, functionally validate, and correct immunodeficiency patient mutations.

项目摘要/摘要