OFF-TARGET RESOURCE CORE

偏离目标的资源核心

• 批准号: 10668616
• 负责人: Xiao Wang
• 金额: $ 106.93万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668616
• 关键词: Address; Biochemical; Bioinformatics; Biological; Biological Assay; Cell model; Center for Translational Science Activities; Chromosomal Rearrangement; Development; Disease; Dose; Elements; Evaluation; Event; Frequencies; Gene Expression; Genetic Variation; Growth; Hepatocyte; Human; Human Genetics; Human Genome; Hybrids; Industry; Insertional Mutagenesis; Laboratories; Lead; Location; Maps; Metabolic Diseases; Methodology; Methods; Modeling; Mucopolysaccharidosis I; New Zealand; Optics; Patients; Pennsylvania; Phenylketonurias; Program Development; Recommendation; Research; Research Design; Research Personnel; Research Project Grants; Resources; Risk; Services; Site; Therapeutic; Time; Tyrosinemias; United States Food and Drug Administration; Universities; Variant; Work; Writing; adeno-associated viral vector; base editing; candidate identification; case-by-case basis; cell type; delivery vehicle; design; disease-causing mutation; gene therapy; genome editing; genome integrity; genome-wide analysis; genotoxicity; high risk; in silico; novel strategies; off-target site; postnatal; preclinical development; preclinical safety; preclinical study; prenatal; safety assessment; tool

PROJECT SUMMARY Off-target editing analyses will be so fundamental to the development of our therapeutic leads, regardless of the disease treated—whether phenylketonuria (Lead Project 1), hereditary tyrosinemia type 1 (Project 2), or mucopolysaccharidosis type I (Project 3)—and so integral to any IND applications that ultimately emerge from the Projects, that we are proposing an Off-Target Resource Core that will serve all three Research Projects. This Resource Core will provide services that are directly aligned with the preclinical studies that are recommended by the U.S. Food and Drug Administration (FDA) Draft Guidance for Industry on Human Gene Therapy Products Incorporating Human Genome Editing, namely: (1) identification of on-target and off-target editing activity, including the type, frequency, and location of all off-target editing events, taking into account human genetic variation; (2) assessment of genomic integrity, including chromosomal rearrangements, large insertions, or large deletions; and (3) evaluation of the biological consequences associated with off-target editing.

项目摘要 脱靶编辑分析对于我们的治疗线索的发展将是至关重要的， 治疗的疾病-无论是苯丙酮尿症（牵头项目1），遗传性酪氨酸血症1型（项目2），或 I型粘多糖样变性（项目3）-因此对于最终出现的任何IND申请都是不可或缺的。 项目，我们提出了一个脱靶资源核心，将服务于所有三个研究项目。 该资源核心将提供与临床前研究直接一致的服务， 美国食品药品监督管理局（FDA）《人类基因产业指南草案》推荐 用于人类基因组编辑的治疗产品，即：（1）识别靶向和脱靶 编辑活动，包括所有脱靶编辑事件的类型、频率和位置，同时考虑到 人类遗传变异;（2）评估基因组完整性，包括染色体重排，大 插入或大缺失;和（3）评估与脱靶编辑相关的生物学后果。