Epigenome Editing Technologies for Treating Diverse Disease

用于治疗多种疾病的表观基因组编辑技术

• 批准号: 9973203
• 负责人: Charles A. Gersbach
• 金额: $ 38.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973203
• 关键词: Address; Adoption; Algorithms; Angelman Syndrome; Animal Disease Models; BCAR1 gene; Bacterial Genome; Bioinformatics; Biological Assay; Biology; CRISPR/Cas technology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Custom; DNA; DNA Methylation; DNA Repair; DNA Sequence; DNA Sequence Alteration; Disease; Disease Progression; Enzymes; Epigenetic Process; Gene Expression; Gene Expression Regulation; Gene Transduction Agent; Genes; Genetic; Genetic Transcription; Genome; Genome engineering; Genomics; Goals; Guide RNA; Health; Hereditary Disease; Heritability; Higher Order Chromatin Structure; Histones; Human; Immunity; Individual; Inherited; Modification; Mutation; Neuromuscular Diseases; Nucleic Acids; Open Reading Frames; Outcome; Pathology; Population; Prader-Willi Syndrome; Primary Lateral Sclerosis; Property; Proteins; RNA; Rare Diseases; Risk; Safety; Sampling; Site; Somatic Cell; Specificity; Structure; System; Technology; Testing; Therapeutic; Translating; Variant; Viral; Viral Vector; Work; adeno-associated viral vector; base; biological research; biomaterial compatibility; clinical translation; epigenetic regulation; epigenome editing; epigenomics; experimental study; gene therapy; genome editing; genome wide association study; genome-wide; histone modification; human disease; human pathogen; immunogenic; immunogenicity; improved; in vivo; mouse model; next generation; novel; nuclease; off-target mutation; preclinical development; programs; somatic cell gene editing; therapeutic target; tool

The recent revolution in novel nucleic acid-targeting systems has generated incredible opportunities for treating disease by targeted manipulation of DNA and RNA. While the emphasis thus far has largely been on genome editing to treat rare, inherited disorders, this represents only one mechanism by which these DNA-targeting tools can be applied to improve human health. In fact, a significantly broader set of pathologies can be addressed by modulating gene regulation and epigenetic states, in contrast to altering underlying DNA sequences. Moreover, this approach has a number of advantages with respect to efficiency, safety, and reversibility. While several studies have demonstrated proof-of-principle that in vivo somatic cell epigenome editing can be used to program cell phentoypes and modulate therapeutic targets, there are a number of challenges that must be overcome to prepare this technology for treatment of human disease. First, an ideal DNA-targeting system that is facile and broadly applicable has yet to be developed. While CRISPR-Cas9 systems have dramatically transformed genome engineering, their application for human epigenome editing is limited by specificity, incompatibility with size-restricted viral vectors, and pre-existing immunity in the human population. Therefore, we will mine bacterial genomes for novel small CRISPR-Cas9/Cas12 systems that meet these criteria for in vivo epigenome editing. We will examine genome-wide specificity of epigenomic modifications with unbiased assays and assess both induced immunity in mouse models and pre-existing immunity in human samples. Second, it remains unclear in the field of epigenome editing which epigenetic modifications are necessary and sufficient to achieve desired outcomes in gene expression and genome structure. We will complete a comprehensive analysis of the relationship between epigenetic states and epigenome editing activity to develop a set of rules for achieving corresponding changes in gene expression. Finally, we will validate these epigenome editing tools in vivo in a set of pilot experiments in mouse models of neuromuscular disease encompassing a representative set of epigenomic states. In close collaboration with the Somatic Cell Genome Editing Consortium, this work will prepare epigenome editing technology for human clinical translation in which it may have a transformative effect on a broad array of both rare and common disease.

最近新型核酸靶向系统的革命为治疗提供了令人难以置信的机会