Gene product delivery by engineered somatic cells

工程体细胞传递基因产物

• 批准号: 7270133
• 负责人: JOY A. PHILLIPS
• 金额: $ 28.11万
• 依托单位: SIDNEY KIMMEL CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270133
• 关键词: Address; Adenosine; Adult; Animal Disease Models; Animals; Antibody Formation; Beds; Biomedical Engineering; Bone Marrow; Cell Count; Cell Line; Cells; Characteristics; Child; Condition; Data; Deficiency Diseases; Development; Disease; Disease model; Doctor of Medicine; Doctor of Philosophy; Dose; Engineered Gene; Engineering; Environment; Erythropoietin; Exhibits; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Functional disorder; Future; Gene Delivery; Gene Expression; Genes; Genetic; Germ Cells; Gifts; Hemophilia A; Human; Immune response; Immunologics; Immunosuppression; Implant; Inherited; Injection of therapeutic agent; Intravenous; Kidney; Life; Liver; Location; Measures; Methods; Modeling; Modification; Monitor; Mus; NIH Program Announcements; Nature; Numbers; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Placement; Plasma; Plasmid Cloning Vector; Population; Proteins; Protocols documentation; Replacement Therapy; Research; Research Personnel; Secondary to; Single-Gene Defect; Site; Somatic Cell; Spleen; Stromal Cells; System; Therapeutic; Therapeutic Effect; Therapeutic immunosuppression; Thymus Gland; Toxic effect; Transfection; Transgenes; Viral; Work; base; clinically relevant; cytokine; diabetic; enzyme deficiency; gene delivery system; hormone deficiency; human F8 protein; implantation; inhibitor/antagonist; neutralizing antibody; novel; pointed protein; programs; promoter; research study; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): This R21 application is in response to the program announcement PA-03-058. The stated objective of this program announcement is to invite applications in exploratory or developmental bioengineering research (EBRG). One listed example of bioengineering research is: Research on drug, gene, or cellular therapeutic delivery systems. This proposal addresses this example. The ideal gene product delivery system would have four main characteristics. (1) It should be delivered with high efficiency; (2) it should exhibit prolonged gene expression (3) it should be show no toxicity; and (4) it should be applicable to the entire patient population without any need for customization. Working in a murine model, we propose to develop a gene delivery system that meets all these requirements. The proposed therapy involves the injection of an MHC-mismatched, transgene-expressing stromal cell line into the thymus. We will establish whether the recipient mice are tolerant to the injected cell line, despite the MHC mismatch, due to the unique nature of the thymic microenvironment (point 4 above). We will examine the recipients to confirm that the injected cells remained at the site of injection (point 1), and we will monitor long-term expression of the gene product (point 2) while looking for any possible pathology related to presence of the delivery cells in the thymus (point 3). Long term gene product delivery following intrathymic injection of transgene-expressing cells could revolutionize treatment of a number of single gene defect disorders.

描述(申请人提供)：本R21申请是对项目公告PA-03-058的回应。该计划声明的目标是邀请在探索性或开发性生物工程研究(EBRG)方面的申请。生物工程研究的一个例子是：药物、基因或细胞治疗递送系统的研究。这项建议针对的是这个例子。理想的基因产品递送系统应该具有四个主要特征。(1)它应该以高效的方式提供；(2)它应该表现出长时间的基因表达；(3)它应该没有毒性；(4)它应该适用于整个患者群体，而不需要任何定制。在小鼠模型中，我们建议开发一种满足所有这些要求的基因递送系统。建议的治疗包括将MHC不匹配的、转基因表达的基质细胞系注射到胸腺。我们将确定由于胸腺微环境的独特性质(上文第4点)，尽管MHC不匹配，但受体小鼠是否对注射的细胞系具有耐受性。我们将检查受者以确认注射的细胞仍留在注射部位(点1)，我们将监测基因产物的长期表达(点2)，同时寻找与胸腺中传递细胞的存在相关的任何可能的病理(点3)。在胸腺内注射转基因表达细胞后的长期基因产品注射可能会彻底改变一些单基因缺陷疾病的治疗。