Development of self-delivering RNAi targeted to PTEN for treatment of spinal cord injury

开发针对 PTEN 的自传递 RNAi 用于治疗脊髓损伤

• 批准号: 9343319
• 负责人: Lisa J McKerracher
• 金额: $ 73.58万
• 依托单位: BIOAXONE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9343319
• 关键词: Adult; Aftercare; Animals; Astrocytes; Axon; Biochemical; Biological Assay; Biology; Blood specimen; Cell Line; Cell Survival; Cells; Chemistry; Clinical; Clinical Chemistry; Clinical Research; Coagulation Process; Control Groups; Contusions; Corticospinal Tracts; Data; Databases; Development; Distal; Dose; Drug Delivery Systems; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Family suidae; Female; Formulation; Funding; Future; Goals; Growth; Hematology; Histologic; Human; Hybrids; In Vitro; Injury; Interferons; Knockout Mice; Label; Lead; Learning; Longevity; Measurable; Measures; Mediating; Messenger RNA; Methods; Modeling; Modification; Molecular; Motor Neurons; Natural regeneration; Nervous System Trauma; Neuraxis; Neuroglia; Neuronal Differentiation; Neurons; Nucleic Acids; Operative Surgical Procedures; Outcome; PTEN gene; PTEN protein; Pathology; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Phase; Play; Protein phosphatase; Proteins; RNA Interference; Rattus; Recovery; Recovery of Function; Regulatory Pathway; Research; Rodent; Role; Route; Safety; Sequence Homology; Serotonin; Serum; Signal Transduction; Site; Small Business Innovation Research Grant; Spinal Cord; Spinal cord injury; Technology; Testing; Therapeutic; Time; Tissue Sample; Toxic effect; Translating; Translations; Traumatic injury; Walking; Western Blotting; axon regeneration; axonal sprouting; base; cell type; efficacy study; experience; experimental study; foot; immunocytochemistry; improved; in vivo; in vivo regeneration; injured; knock-down; mRNA Expression; male; motor function recovery; novel; novel therapeutics; nuclease; phosphorothioate; pre-clinical research; prevent; programs; protein expression; response; safety and feasibility; safety study; therapeutic development

Studies on axon regeneration and recovery in rodents have revealed that the spinal cord is not hard wired and “learning” can occur in spinal cord circuits. Compounds that elicit axonal regeneration and sprouting help plasticity in the spinal cord and dramatically improve recovery from traumatic injury, at least in rodents. Intrinsic signals that progress with normal neuronal differentiation play a significant role in preventing axon regeneration. Several intrinsic negative regulators of regeneration have been identified through studies of knock-out mice. Suppression of synthesis of PTEN protein can promote axon regeneration and recovery of motor function in adult rodents. There has been a concerning lack of translation in SCI research for the most promising targets, and therefore we decided to create a compound with potential for therapeutic development. We chose the technology of self-deliverable RNA interference (sd-rxRNAi) because of the simplicity and proven efficacy of in vivo delivery to the central nervous system. BA- 434 as a novel sd-rxRNA that targets mRNA encoding PTEN and suppress the expression of PTEN protein. It has sequence homology to rat, pig and human, and was selected from 20 that we screened. We propose to further development of BA-434 and carry out IND-enabling safety and efficacy experiments to translate these findings to clinical study. We will optimize stability of BA-434, and dose and efficacy in spinal cord injury models. We will also confirm appropriate drug delivery in pig spinal cord because the size of pig spinal cord better approximates the size of human spinal cord. The proposed research will form the basis of non-GLP safety and efficacy studies in support of an IND application.

关于啮齿动物的轴突再生和恢复的研究表明，脊髓 不是硬有线，脊髓电路可能会发生“学习”。引起的化合物 轴突再生和发芽有助于脊髓中的可塑性 至少在啮齿动物中改善创伤损伤的恢复。进展的内在信号 正常的神经元分化在防止轴突中起重要作用 再生。已经确定了几个固有的负面调节因子 通过研究淘汰小鼠。抑制PTEN蛋白的合成可以 促进成年啮齿动物中运动功能的轴突再生和恢复。有 关于最有希望的目标的SCI研究中缺乏翻译，以及 因此，我们决定创建具有治疗性开发潜力的化合物。 我们选择了自由交付的RNA干扰（SD-RXRNAI）的技术 体内传递到中枢神经系统的简单性和可证明的有效性。 ba- 434作为一种新型的SD-RXRNA，靶向编码PTEN并抑制的mRNA PTEN蛋白的表达。它与老鼠，猪和人具有序列同源性，是 从我们筛选的20中选择。我们建议进一步开发BA-434和 进行辅助安全性和效率实验，将这些发现转化为 临床研究。我们将优化BA-434的稳定性，并在脊髓中的剂量和效率 伤害模型。我们还将在猪脊髓中确认适当的药物输送 猪脊髓的大小更好近似于人脊髓的大小。这 拟议的研究将构成非GLP安全和效率研究的基础 IND应用程序。