Next generation gamma Peptide Nucleic Acids (yPNAs) for the treatment of ischemic stroke

用于治疗缺血性中风的下一代伽马肽核酸 (yPNA)

• 批准号: 10057635
• 负责人: Rajkumar Verma
• 金额: $ 46.37万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057635
• 关键词: Affect; Affinity; Aftercare; American; Amyloidosis; Animal Model; Animals; Area; Base Pairing; Behavioral; Binding; Biochemical; Biodistribution; Biological Assay; Biological Markers; Biology; Brain; Cell Culture Techniques; Chemistry; Complementary RNA; Conserved Sequence; Data; Disease; Drug Formulations; Drug Kinetics; Drug Targeting; Effectiveness; Gelshift Analysis; Gene Expression; Glycine; Glycolates; Goals; Histologic; House mice; Individual; Inherited; Injury; Intervention; Ischemic Stroke; Laboratories; Laboratory culture; Lymphoma; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Middle Cerebral Artery Occlusion; Modeling; Modernization; Molecular Conformation; Molecular Target; Mus; Nanotechnology; Neuraxis; Nucleic Acids; Operative Surgical Procedures; Organ; Peptide Hydrolases; Peptide Nucleic Acids; Pharmaceutical Preparations; Pharmacological Treatment; Polyneuropathy; Population; Prealbumin; Property; Quality Control; Reagent; Recovery; Scientist; Series; Site; Small Interfering RNA; Social isolation; Solubility; Specificity; Spinal Muscular Atrophy; Stroke; Technology; Testing; Therapeutic; Translating; Treatment Efficacy; United States; Untranslated RNA; Variant; Vertebral column; aged; base; biophysical properties; disability; drug candidate; drug development; effective therapy; hypolipidemia; improved; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; mouse model; multidisciplinary; nanoformulation; nanoparticle; nanoparticle delivery; neurovascular; next generation; novel; nucleic acid analog; phosphodiester; post stroke; pre-clinical; response; sex; social; stroke model; stroke risk; stroke therapy; synthetic construct; synthetic nucleic acid; targeted treatment; tool

Summary: Micro RNAs (miRNAs) are a class of short non-coding RNAs that have been identified as potentially powerful tools for the study and treatment of many diseases, including ischemic stroke. Due to their conserved sequence, targeting specific miRNAs using synthetic anti-microRNA (anti-miR) reagents makes them attractive targets for drug development. We recently established that stroke and factors modifying stroke responses, such as social isolation, can modulate miRNAs, especially miR-141-3p. Hence, miR-141-3p represents a promising new molecular target for stroke therapy. Therefore, by developing therapeutics tailored to antagonize miR-141-3p, we hope to generate an effective therapy for stroke. Herein, we propose a multi- disciplinary project that applys modern technology to advance a promising stroke therapy that targets miR-141- 3p using novel next-generation anti-miR-based tools. In the past, we demonstrated that nanotechnology- delivered peptide nucleic acid (PNA)-based miRNA inhibitors can target miR-155 for lymphoma therapy. Unlike most nucleic acids, PNAs are synthetic DNA mimics in which the phosphodiester backbone is substituted with a neutral N-(2-aminoethyl) glycine backbone. PNAs can bind single-stranded targets with high specificity and affinity and are not susceptible to proteases, making PNAs ideal molecules for targeting miRNAs. To improve the effectiveness of anti-miR PNAs further, we will exploit a new class of PNA analogs designated gamma PNAs (PNAs), which are conformationally pre-organized and so have advantageous binding and solubility properties that should increase their effectiveness as anti-miR agents. For delivery, we will employ poly (lactic- co-glycolic acid) (PLGA)-based nanoformulations. As proof of principle for our stable next generation PNA- based anti-miR-141-3p as a stroke therapeutic, we propose to test delivery and efficacy in stroke-based diseased mouse models. Here, we will pursue two independent specific aims: 1) Synthesis and quality control analysis of an array of PNA-based anti-miR-141-3p in cell culture-based assays; and 2) Test in vivo efficacy of PNA-based anti-miR-141-3p variants in a diseased mouse model. We have assembled an interdisciplinary team to achieve our goals, with expertise in nucleic acid chemistry, drug formulation, and disease biology.

总结： 微小RNA（microRNAs，miRNAs）是一类短的非编码RNA，具有潜在的功能 用于研究和治疗许多疾病的工具，包括缺血性中风。由于其保守的 序列，使用合成的抗microRNA（anti-miR）试剂靶向特定的miRNAs使其具有吸引力 药物开发的目标。我们最近发现中风和改变中风反应的因素， 例如社会隔离，可以调节miRNA，尤其是miR-141- 3 p。因此，miR-141- 3 p代表了一种 有望成为中风治疗的新分子靶点。因此，通过开发针对 拮抗miR-141- 3 p，我们希望产生一种有效的治疗中风的方法。在此，我们提出了一个多- 应用现代技术推进靶向miR-141的有前景的中风治疗的学科项目- 3 p使用新的下一代基于抗miR的工具。在过去，我们证明了纳米技术- 递送的基于肽核酸（PNA）的miRNA抑制剂可以靶向miR-155用于淋巴瘤治疗。不像 大多数核酸，PNA是合成的DNA模拟物，其中磷酸二酯骨架被取代， 中性N-（2-氨乙基）甘氨酸骨架。PNA可以以高特异性结合单链靶标， 它们具有亲和性，对蛋白酶不敏感，使PNA成为靶向miRNA的理想分子。提高 进一步，我们将开发一类新的PNA类似物，命名为γ PNAs（PNAs），其在构象上是预组织的，因此具有有利的结合和溶解性 这些特性应该增加它们作为抗miR剂的有效性。我们将使用聚乳酸- 共-乙醇酸）（PLGA）基纳米制剂。作为我们稳定的下一代DNA的原理证明- 基于抗miR-141- 3 p作为中风治疗药物，我们建议在基于抗miR-141- 3 p的中风治疗中测试递送和功效。 患病小鼠模型。在这里，我们将追求两个独立的具体目标：1）合成和质量控制 在基于细胞培养的测定中分析基于cDNA的抗miR-141- 3 p阵列;和2）测试体内功效 在患病小鼠模型中的基于cDNA的抗miR-141- 3 p变体。我们召集了一个跨学科的 我们的团队拥有核酸化学、药物配方和疾病生物学方面的专业知识，致力于实现我们的目标。