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.

项目摘要/摘要 心力衰竭(HF)是一种常见的疾病，其发病率和死亡率都有很好的记录，影响 全球约有2300万人，其中包括美国的600万人。目前的HF药物，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)治疗这些症状 心力衰竭与疾病的根本原因，包括导致肥大的应激心肌 心肌细胞和内皮细胞炎症。 CaMKIIδ是一种信号分子，调节参与兴奋收缩偶联的细胞通路 以及心脏的松弛事件和与心肌肥厚相关的基因的转录激活， 炎症和心律失常。如果不纠正，CaMKIIδ调节的变化最终会导致功能障碍 心肌和心衰。STTR第一阶段项目的目标是通过提供以下方式解决心衰的根本原因 MiRNA下调心肌细胞CaMKIIδ的过度表达和/或激活，因为 可能会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来有效地抑制CaMKIIδ的表达。 活着。然后将该miRNA连接到专有的细胞穿透肽--心脏靶向肽 (CTP)，由Vivarc治疗公司开发。这将产生一种CTP-miRNA结合物，它将提供 核苷酸对心肌细胞具有特异性和直接性。CTP是一种新型的合成肽，它已转导(I) 活体正常小鼠心脏(注射后15分钟摄取峰值)，(Ii)移植的人心脏组织，以及 (3)人源性IPSC搏动心肌细胞。CTP已显示出强大的正常转导功能 心肌细胞，而不包括肌成纤维细胞、内皮细胞和瘢痕组织中的成纤维细胞。到目前为止， CTP结合物已转导心肌细胞携带各种不同的完整货物，如放射性同位素、核 酸，其他多肽，和生物素-链霉亲和素复合体一样大的偶联物。该团队的初步数据 已经表明CTP完全能够以类似的方式携带miRNA。 假设CTP-miRNA将把miRNA传递给过度表达CaMKIIδ的心肌细胞， 从而使受损的心肌细胞恢复正常功能。其目的是：1)提供特定的miRNAs 给心力衰竭小鼠心脏注射，以证明其逆转心力衰竭生理的有效性和2)测试 双标记CTP-miRNA在体内的生物分布。 第二阶段计划包括在更大的心衰和IND动物模型中进行优化CTP-miRNA的研究。 使研究能够支持研究新药(IND)提交以供批准一期临床 审判。一旦获得批准，这种治疗方法可能会被开给患有心肌肥厚的心衰患者， 炎症和心律失常。