Using Cardiac Targeting Peptide to deliver miRNA for molecular reversal of heart failure

使用心脏靶向肽传递 miRNA 以分子逆转心力衰竭

• 批准号: 10481720
• 负责人: G IAN GALLICANO
• 金额: $ 28.47万
• 依托单位: VIVASC THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-13 至 2024-07-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481720
• 关键词: Address; Adult; Affect; Amino Acids; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Apoptosis; Arrhythmia; Biodistribution; Biological Assay; Biotin; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cell membrane; Cell physiology; Cells; Cicatrix; Complex; Coupling; Data; Development; Disease; Dose; Endothelial Cells; Endothelium; Environment; Enzymes; Epinephrine; Event; Exposure to; Family; Fibroblasts; Gene Activation; Gene Expression; Genes; Goals; Health; Heart; Heart Hypertrophy; Heart failure; Human; In Vitro; Individual; Inflammation; Injections; Intravenous; Investigational Drugs; Kidney; Knock-out; Knowledge; Label; Left; Legal patent; Letters; Link; Liver; Logic; Longevity; Luciferases; MicroRNAs; Molecular; Morbidity - disease rate; Morphology; Mus; Myocardium; Myofibroblast; Nucleic Acids; Nucleotides; Organ; Pathologic; Pathway interactions; Patients; Pattern; Peptides; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phenotype; Physiological; Physiology; Plant Roots; Prevalence; Process; Protein Isoforms; Publishing; Quality of life; Radioisotopes; Recovery; Relaxation; Role; Safety; Signaling Molecule; Small Business Technology Transfer Research; Streptavidin; Stress; TXN gene; Technology; Testing; Therapeutic; Tissues; Transcriptional Activation; Treatment Failure; Western Blotting; Wild Type Mouse; Work; calmodulin-dependent protein kinase II; cardiogenesis; cell injury; clinical development; commercial application; commercialization; cost; cyanine dye 5; disulfide bond; improved; in vivo; in vivo evaluation; in vivo imaging system; induced pluripotent stem cell; mortality; mouse model; novel; overexpression; pre-clinical; side effect; symptom treatment; synthetic peptide; targeted treatment; technological innovation; therapeutic miRNA; therapeutically effective; time use; uptake; vector

PROJECT SUMMARY/ABSTRACT Heart failure (HF) is a common disease with well-documented morbidity and mortality that affects approximately 23 million people globally, including 6 million in the US. Current HF medications such as Angiotensin Converting Enzyme (ACE) Inhibitors or Angiotensin Receptor Blockers (ARBs) treat the symptoms of HF versus the root cause of the disease, which includes stressed myocardium that leads to hypertrophic cardiomyocytes and endothelial inflammation. CaMKIIδ is a signaling molecule that regulates cellular pathways involved in excitation‑contraction coupling and relaxation events in the heart and transcriptional activation of genes related to cardiac hypertrophy, inflammation, and arrhythmias. If left uncorrected, CaMKIIδ‑regulated changes culminate in a dysfunctional myocardium and HF. The goal of this STTR Phase I project is to address this root cause of HF by delivering miRNA to cardiomyocytes to down-regulate the over-expression and/or activation of CaMKIIδ because this may allow damaged cardiomyocytes to regain normal function. To achieve this goal, a specific miRNA will be selected that effectively inhibits the expression of CaMKIIδ in vivo. This miRNA will then be conjugated to the proprietary cell penetrating peptide, Cardiac Targeting Peptide (CTP), developed by Vivasc Therapeutics. This will create a CTP-miRNA conjugate that will deliver this nucleotide specifically and directly to cardiomyocytes. CTP is a novel, synthetic peptide that has transduced (i) normal mouse hearts in vivo (peak uptake at 15 minutes after injection), (ii) explanted human heart tissue, and (iii) human derived iPSC beating cardiomyocytes. CTP has demonstrated robust transduction of normal cardiomyocytes while sparing myofibroblasts, endothelial cells, and fibroblasts present in scar tissue. To date, CTP conjugates have transduced cardiomyocytes carrying intact cargoes as diverse as radioisotopes, nucleic acids, other peptides, and conjugates as large as the biotin-streptavidin complex. The team’s preliminary data has shown that CTP is fully capable of carrying miRNA in a similar manner. The hypothesis is that CTP-miRNA will deliver miRNA to cardiomyocytes that are over expressing CaMKIIδ, thereby allowing damaged cardiomyocytes to regain normal function. The aims are: 1) deliver specific miRNAs to the hearts of HF mouse models to demonstrate their efficacy in reversing HF physiology and 2) test the in vivo biodistribution of CTP-miRNA using a dual-labeled CTP-miRNA. Phase II plans include conducting studies of optimized CTP-miRNA in larger animal models of HF and IND- enabling studies to support an Investigational New Drug (IND) submission for approval of a Phase 1 clinical trial. Upon approval, this treatment could potentially be prescribed to HF patients with cardiac hypertrophy, inflammation, and arrhythmias.

项目概要/摘要 心力衰竭（HF）是一种常见疾病，其发病率和死亡率均有充分记录，影响 全球约有 2300 万人，其中美国有 600 万人。目前的心力衰竭药物，例如 血管紧张素转换酶 (ACE) 抑制剂或血管紧张素受体阻滞剂 (ARB) 可治疗症状 心力衰竭的原因与疾病的根本原因，其中包括导致肥厚的心肌受压 心肌细胞和内皮炎症。 CaMKIIδ 是一种信号分子，调节参与兴奋-收缩耦合的细胞通路 心脏的松弛事件以及与心脏肥大相关的基因的转录激活， 炎症和心律失常。如果不加以纠正，CaMKIIδ 调节的变化最终会导致功能失调 心肌和心力衰竭。 STTR 第一阶段项目的目标是通过提供解决心衰的根本原因 miRNA 作用于心肌细胞以下调 CaMKIIδ 的过度表达和/或激活，因为这 可以使受损的心肌细胞恢复正常功能。 为了实现这一目标，将选择一种特定的 miRNA 来有效抑制 CaMKIIδ 的表达。 体内。然后，该 miRNA 将与专有的细胞穿透肽、心脏靶向肽缀合 （CTP），由 Vivasc Therapeutics 开发。这将创建一个 CTP-miRNA 缀合物，该缀合物将提供这种作用 核苷酸特异性地直接作用于心肌细胞。 CTP 是一种新型合成肽，已转导 (i) 体内正常小鼠心脏（注射后 15 分钟达到峰值吸收），(ii) 移植的人类心脏组织，以及 (iii) 人源 iPSC 跳动心肌细胞。 CTP 已表现出对正常细胞的强大转导作用 心肌细胞，同时保留疤痕组织中存在的肌成纤维细胞、内皮细胞和成纤维细胞。迄今为止， CTP 缀合物已转导心肌细胞，其携带完整的货物，如放射性同位素、核酸 酸、其他肽和与生物素-链霉亲和素复合物一样大的缀合物。团队初步数据 已经表明CTP完全能够以类似的方式携带miRNA。 假设 CTP-miRNA 将 miRNA 传递至过度表达 CaMKIIδ 的心肌细胞， 从而使受损的心肌细胞恢复正常功能。目标是：1) 传递特定的 miRNA 注入心力衰竭小鼠模型的心脏，以证明其在逆转心力衰竭生理学方面的功效，并 2) 测试内部 使用双标记 CTP-miRNA 进行 CTP-miRNA 的体内生物分布。 II 期计划包括在 HF 和 IND 的大型动物模型中进行优化的 CTP-miRNA 研究 使研究能够支持研究性新药 (IND) 提交以批准 1 期临床 审判。一旦获得批准，这种治疗方法可能会用于患有心脏肥大的心力衰竭患者， 炎症和心律失常。