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)

基本信息

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
项目类别：
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

项目摘要

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.

概括：微RNA（miRNA）是一类简短的非编码RNA，已被确定为潜在强大研究和治疗许多疾病的工具，包括缺血性中风。由于他们的保守序列，使用合成抗微虫（抗MIR）试剂靶向特定的miRNA使其具有吸引力药物开发目标。我们最近确定了中风和修改中风反应的因素，例如社会隔离，可以调节miRNA，尤其是mir-141-3p。因此，miR-141-3p代表有希望的中风治疗的新分子靶标。因此，通过开发量身定制的治疗与miR-141-3p对抗，我们希望对中风产生有效的疗法。在此，我们提出了一个多采用现代技术来推进有前途的中风疗法的纪律项目，该疗法针对miR-141-- 3P使用新型的下一代反MIR工具。过去，我们证明了纳米技术 - 基于肽核酸（PNA）的miRNA抑制剂可以靶向miR-155进行淋巴瘤治疗。与众不同大多数核酸，PNA是合成的DNA模拟物，其中磷酸二酯主链被用中性N-（2-氨基乙基）甘氨酸主链。 PNA可以以高特异性结合单链目标，并且亲和力，不容易受到蛋白酶的影响，使PNAS成为靶向miRNA的理想分子。改进抗MIR PNA的有效性进一步，我们将利用一类新的PNA类似物指定的PNA类似物 PNA（PNA），在构象上进行了预先组织，因此具有有利的结合和可溶性应提高其作为抗MIR药物的有效性的特性。为了交付，我们将采用poly（乳酸 - 基于Co-乙醇酸）（PLGA）基于纳米成型。作为我们稳定的下一代原理证明PNA- 基于抗MIR-141-3P作为中风疗法，我们建议测试基于中风的交付和效率患病的鼠标模型。在这里，我们将追求两个独立的特定目标：1）合成和质量控制基于细胞培养的测定中的一系列基于PNA的抗MIR-141-3P阵列的分析； 2）在体内效率测试在失效的小鼠模型中基于PNA的抗MIR-141-3P变体。我们组装了一个跨学科团队以实现我们的目标，并具有核酸化学，药物配方和疾病生物学方面的专业知识。