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，有据可查的发病率和死亡率影响 全球约有2300万人，其中包括美国600万人。当前的HF药物，例如 血管紧张素转化酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARB）处理符号 HF与该疾病的根本原因，其中包括压力心肌，导致肥厚 心肌细胞和内皮炎症。 CAMKIIδ是一种信号分子，可调节与兴奋 - 诱使耦合有关的细胞途径 和心脏的放松事件和与心脏肥大有关的基因的转录激活， 炎症和心律不齐。如果未纠正 心肌和HF。该STTR I阶段项目的目标是通过交付来解决HF的这一根本原因 miRNA到心肌细胞，以下调Camkiiδ的过表达和/或激活 可能使受损的心肌细胞保持正常功能。 为了实现这一目标，将选择一个特定的miRNA，可有效抑制CaMKIIΔ在 体内。然后将此miRNA连接到专有细胞穿透肽，心脏靶向肽 （CTP），由Vivasc Therapeutics开发。这将创建一个CTP-miRNA结合物，将提供此功能 核苷酸专门直接针对心肌细胞。 CTP是一种已翻译的新型合成肽（i） 正常的小鼠心脏在体内（注射后15分钟的峰值吸收），（ii）养育人心脏组织和 （iii）人类衍生的IPSC跳动心肌细胞。 CTP已显示出正常的强大转移 心肌细胞在疤痕组织中保留肌纤维细胞，内皮细胞和成纤维细胞时。迄今为止， CTP共轭物已翻译出携带完整货物的心肌细胞，如放射性同位素，核素 酸，其他肽和偶联物与生物素 - 链霉亲和素复合物一样大。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。 假设是CTP-MIRNA会向超过表达CAMKIIδ的心肌细胞传递miRNA， 从而允许受损的心肌细胞保持正常功能。目的是：1）提供特定的miRNA 向HF小鼠模型的心脏展示其在逆转HF生理学方面的效率，2）测试 使用双标记的CTP-MIRNA对CTP-MIRNA的体内生物分布。 第二阶段计划包括在HF和IND-较大的动物模型中对优化的CTP-MIRNA进行研究 使研究能够支持研究性新药（IND）批准1期临床 审判。经过批准，这种治疗可能会针对心脏肥大的HF患者处方 炎症和心律不齐。