Engineering epigenetic therapy for sickle cell disease

镰状细胞病的工程表观遗传学治疗

• 批准号: 8752559
• 负责人: CARL D NOVINA
• 金额: $ 86.5万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2019-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752559
• 关键词: Adult; Age; Biochemical; Biomedical Research; Birth; Blood Vessels; CD34 gene; Cell division; Chemokine (C-C Motif) Receptor 5; Clinical Trials; Custom; DNA; DNA Binding; DNA Binding Domain; DNA Methylation; DNA Modification Process; Disease; Ectopic Expression; Engineering; Enzymes; Epigenetic Process; Erythrocytes; Fetal Hemoglobin; Gene Activation; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Engineering; Globin; HIV; Hemoglobin; Histone Acetylation; Histones; Individual; Investigational New Drug Application; Knock-out; Lead; Literature; Medical; Methylation; Modification; Mutation; Neoadjuvant Therapy; Pain; Phase I Clinical Trials; Process; Proteins; Resistance; Sickle Cell Anemia; Site; T-Lymphocyte; Technology; Treatment Efficacy; Zinc Fingers; base; demethylation; fetal; gamma Globin; gene correction; gene therapy; homologous recombination; innovation; interest; knockout gene; medical complication; nuclease; programs; research study; restriction enzyme; sickling; technology development; therapeutic gene

DESCRIPTION (provided by applicant): The advent of custom built DNA binding domains fused to restriction enzymes changed the landscape of biomedical research and heralded a new age in gene therapy. This fact is highlighted by Phase I clinical trials in which zinc finger nucleases are being used to knockout the CCR5 receptor in CD34+ T cells of HIV infected individuals to generate HIV-resistant T cells (clinical trial #NCT00842634). In addition to targeted gene knockout, other biomedical applications of the “designer nucleases” are gene correction and gene activation. However, gene correction requires homologous recombination following a DNA cut – a very inefficient process – and current strategies for stable gene activation require constitutive expression of an ectopic protein, limitations that are likely to hinder therapeutic efficacy. In contrast to endogenous gene editing or genetic activation, I propose to develop a platform for epigenetic reprogramming of any locus of interest. As a proof-of-concept for this technology, I propose to engineer site-specific DNA binding module fusions with DNA demethylating enzymes for epigenetic induction of fetal hemoglobin (HbF) for therapy of sickle cell disease (SCD). SCD is caused by mutation of the adult -globin gene which forces red blood cells to sickle and occlude small blood vessels leading to exquisite pain and a wide range of medical complications. Fetal hemoglobin is normally silenced at birth by DNA methylation of the -globin locus as adult hemoglobin increases. Because small increases in HbF can cure this disease, SCD is an optimal application for developing epigenetic re-programming technologies. The major advantage of epigenetic engineering is that successful DNA demethylation of CpGs on both strands will lead to durable HbF-induction, not requiring continuous expression of ectopic proteins. This highly-innovative strategy has no precedent in the SCD literature. Development of this technology will lead to potent and durable HbF-induction therapy for SCD that will become the basis for an investigational new drug application. Moreover, this technology can be adapted to epigenetic reprogramming of other biochemical modifications including DNA methylation and histone acetylation and methylation. Each of these modifications could be targeted for therapeutic gene silencing or activation which will revolutionize molecularly-directed therapy for a variety of diseases.

描述（由申请人提供）：融合到限制性内切酶的定制DNA结合域的出现改变了