MUCOSAL GENE TRANSFER USING DENDRIMER POLYMERS

使用树枝状聚合物进行粘膜基因转移

• 批准号: 2672850
• 负责人: JAMES R. BAKER
• 金额: $ 23.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672850
• 关键词: amines; chemical structure function; disease /disorder model; drug delivery systems; drug design /synthesis /production; gene therapy; inflammation; laboratory mouse; laboratory rat; method development; mucosa; nonhuman therapy evaluation; polymers; pulmonary fibrosis /granuloma; respiratory epithelium; transfection

Recent work in has demonstrated the plyamidoamine dendrimers, a new type of highly branched dendtiric polymer, can b used to mediate the efficient transfer of genetic material into eukaryotic cell. This polymer has a highly defined structure, is inert and non-immunogenic, and binds nucleic acids of any size or structure in a wide variety of conditions. High efficiency DNA transfer has been mediated to a wide variety of cells in vitro using the dendrimer/DNA complexes. These cells have included airway epithelial cells lines. In addition, preliminary evidence suggests that DNA/dendrimer complexes can transfect lung cells in vivo and that DNA complexed to dendrimers has prolonged persistence in vivo. In addition, the unique ability to alter specific parameters in dendrimer structure allows these molecules to be used as probes to examine particular aspects of the transfection of different types of airway epithelial cells. The central hypothesis of this proposal is that unique forms of dendritic polymers will bind and effectively deliver therapeutic nucleic acid molecules to airway mucosal cells in vivo. This form of gene transfer would be employed for the treatment of airway inflammatory diseases an involve the delivery of different forms of therapeutic nucleic acids to alter a variety of inflammatory events. First, a number of different dendrimers will be produced to determine what alterations in polymer design or the conjugation of the polymers to molecules, such carbohydrates, drugs, antibodies, or synthetic peptides, will allow the efficient targeting and transfer of DNA/dendrimer complexes to specific airway epithelial or inflammatory cells. A well defined model of pulmonary fibrosis will then be employed to test the efficacy of genetic intervention using DNA/dendrimer complexes to prevent the development of fibrosis. This proposal is based on work from my laboratory and also studies from other groups that have documented that dendrimers are easily conjugated to targeting molecules and that conjugated dendrimers can efficiently target radionucleotides to cells in vivo. The results of these studies will provide basic information about gene delivery that should allow further refinements in protocols and agents for endobronchial gene transfer.

近年来的研究表明，酰胺胺树状大分子是一种新型的 高度支化的树枝状聚合物，可B介导有效的 将遗传物质转移到真核细胞中。 该聚合物具有 高度确定的结构，是惰性的和非免疫原性的， 任何大小或结构的酸在各种条件下。 高 高效的DNA转移已经被介导到多种细胞中， 使用树枝状聚合物/DNA复合物体外。 这些细胞包括气道 上皮细胞系 此外，初步证据表明， DNA/树枝状聚合物复合物可在体内转染肺细胞， 与树枝状聚合物复合的化合物在体内具有延长的持久性。 此外，本发明还提供了一种方法， 改变树枝状聚合物结构中特定参数的独特能力 允许这些分子被用作探针， 不同类型的气道上皮细胞的转染。的 这一提议的中心假设是， 聚合物将结合并有效地递送治疗性核酸 分子到体内气道粘膜细胞。 这种形式的基因转移 将用于治疗气道炎性疾病， 涉及递送不同形式的治疗性核酸， 改变各种炎症事件。 首先，一些不同的 将生产树枝状聚合物，以确定聚合物设计的变化 或聚合物与分子，如碳水化合物，药物， 抗体或合成肽将允许有效的靶向， 将DNA/树枝状聚合物复合物转移到特定的气道上皮或 炎症细胞 一个定义明确的肺纤维化模型， 用于测试基因干预的有效性， DNA/树枝状聚合物复合物，以防止纤维化的发展。 这 该提案基于我实验室的工作以及其他实验室的研究 已经证明树枝状聚合物很容易与 靶向分子，并且缀合的树枝状聚合物可以有效地靶向 在体内对细胞进行放射性治疗。 这些研究的结果将 提供有关基因传递的基本信息， 用于支气管内基因转移的方案和试剂的改进。