Targeted Delivery of RNAi to Nerve Cells

RNAi 靶向递送至神经细胞

• 批准号: 7404204
• 负责人: ANTHONY A Ferrante
• 金额: $ 14.97万
• 依托单位: PHYSICAL SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404204
• 关键词: Address; Adult; Affect; Animal Model; Antibodies; Biological Assay; Brain Injuries; Carrier Proteins; Cell Line; Cells; Cessation of life; Chemistry; Chimeric Proteins; Contracts; Cytolysis; Cytoplasm; Development; Diphtheria Toxin; Disease; Disease Progression; Disulfide Linkage; Dopamine; Dose; Evaluation; Exhibits; Gel; Goals; Government; Green Fluorescent Proteins; In Vitro; Label; Life; Messenger RNA; Methods; Monitor; Movement; Muscle Rigidity; Neuraxis; Neurodegenerative Disorders; Neurons; Parkinson Disease; Patients; Persons; Phase; Phase I Clinical Trials; Population; Posture; Process; Production; Protein Overexpression; Proteins; Public Health; Purpose; RNA Interference; RNA Sequences; Range; Reporting; Research; Rest Tremor; Signal Transduction; Small Interfering RNA; Substantia nigra structure; Symptoms; System; Technology; Tetanus Toxin; Therapeutic; Toxin Conjugates; Transmembrane Domain; Western Blotting; desire; dopaminergic neuron; fluorescence microscope; immunogenicity; improved; in vivo; mRNA Transcript Degradation; mutant; novel; pars compacta; physical science; protein aggregation; synuclein; targeted delivery; uptake

DESCRIPTION (provided by applicant): Parkinson's disease is a common progressive neurodegenerative disorder that affects 2% of the adult population. The loss of dopamine producing neurons in the substantia nigra pars compacta results in such symptoms as a resting tremor, slow movement, rigidity and unstable posture. The death of the dopaminergic neurons has been proposed to be due to aggregation of the protein 1-synuclein. An improved targeted delivery system to neuronal cells is necessary to improve therapeutic treatment options. Physical Sciences Inc. (PSI) proposes to conjugate a targeted small interfering RNA (siRNA) against 1- synuclein protein to a carrier molecule for specific delivery to neurons. The Phase II effort will develop an effective method for large-scale production of the siRNA conjugate and will evaluate the most efficient mode of in vivo delivery in live animal models. We anticipate that the proposed system will deliver sufficient siRNA to reduce the production of 1-synuclein by at least 80%.Project Narrative Relevance to public health. Limited treatment options are available to patients with Parkinson's disease. 1-Synuclein has been proposed to be a causative agent of deleterious effects of Parkinson's disease. The technology developed during the proposed research will reduce the production of 1-synuclein in nerve cells and should therefore slow the progression of the disease.

描述（由申请人提供）：帕金森病是一种常见的进行性神经退行性疾病，影响2%的成年人。黑质致密部产生多巴胺的神经元的缺失导致静息性震颤、运动缓慢、僵硬和姿势不稳等症状。多巴胺能神经元的死亡被认为是由于蛋白1-突触核蛋白的聚集。改善神经细胞的靶向递送系统是改善治疗选择的必要条件。物理科学公司（PSI）提出了一种针对1-突触核蛋白的靶向小干扰RNA （siRNA）结合到载体分子上，以特异性递送到神经元。第二阶段的工作将开发一种大规模生产siRNA偶联物的有效方法，并将在活体动物模型中评估最有效的体内递送模式。我们预计所提出的系统将提供足够的siRNA，以减少至少80%的1-synuclein的产生。与公共卫生的相关性。帕金森氏症患者的治疗选择有限。1-突触核蛋白已被认为是帕金森氏病的有害影响的致病因子。在拟议的研究中开发的技术将减少神经细胞中1-突触核蛋白的产生，因此应该减缓疾病的进展。