HLS- Cyclic CAR peptide: a targeted therapy for pulmonary hypertension

HLS-环状CAR肽：肺动脉高压的靶向治疗

基本信息

批准号：
9347715
负责人：
PAUL B YU
金额：
$ 30.24万
依托单位：
VASCULAR BIOSCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347715
关键词：
Acute Address Adjuvant Adjuvant Therapy Adverse effects Animals Anti-Inflammatory Agents Anti-inflammatory Bacteriophages Binding Bioavailable Biological Assay Biological Availability Blood Vessels Chronic Combination Drug Therapy Combined Modality Therapy Cyclic Peptides Diagnosis Disease Disease Progression Dose Drug Delivery Systems Drug Kinetics Endothelin Endothelin Receptor Antagonist Endothelium Exhibits FDA approved Formulation Heart failure Homing Hypoxia Immunoassay Lung Lung diseases Mass Spectrum Analysis Modeling Monocrotaline Nitric Oxide Pathway Obstruction Oral Oral Administration Organ Peptides Periodicity Pharmaceutical Preparations Pharmacodynamics Pharmacology Study Pharmacotherapy Phase Physiological Program Development Prostaglandins I Pulmonary Circulation Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary vessels Rattus Resistance Right Ventricular Hypertrophy Safety Sensitivity and Specificity Sequence Homology Serum Sublingual drug administration System Tachyphylaxis Therapeutic Effect Toxic effect Tumor Tissue Tunica Adventitia Vascular Diseases Vascular Endothelium Vascular remodeling Vasodilation Vasodilator Agents Ventricular base cationic antimicrobial protein CAP 37 design efficacy testing functional status hemodynamics improved inhibitor/antagonist intravenous administration mortality nanoparticle novel therapeutics pressure protein aminoacid sequence response sildenafil soft tissue synergism targeted treatment tumor vascular bed

项目摘要

PUBLIC ABSTRACT This project, in response to announcement HLS16-06, describes a development program for CARSKNKDC (CAR), a synthetic cyclic peptide that selectively targets diseased pulmonary vascular endothelium and enhances the therapeutic effect of vasodilator therapies, for the treatment of pulmonary hypertension (PH). PH is a disorder of elevated pulmonary vascular resistance characterized by progressive thickening and obliteration of resistance-determining vessels of the pulmonary circulation. Despite current therapies, survival following the diagnosis of PH remains slightly better than 50% at 5 years, with mortality a result of disease progression and right heart failure. Vasodilator therapies acting upon endothelin, prostacyclin, and nitric oxide pathways modestly improve functional status, but are limited by systemic side effects, toxicity, and tachyphylaxis. No current therapy selectively targets the diseased pulmonary circulation. CAR, whose peptide sequence has high sequence homology to protein heparin- binding domains, was identified by a phage screen for its enhanced binding to the vasculature of soft tissue wounds. We have demonstrated that CAR accumulates in the endothelium and adventitia of pulmonary vessels in animals with PH, but not systemic vessels, and not the pulmonary vessels of normal animals. When given with systemic vasodilator therapies, CAR potentiates selective vasodilatation of the pulmonary vascular bed without increasing systemic vasodilation. CAR peptide appears to enhance the delivery of drugs to diseased vessels by a co-administration effect without requiring conjugation to drugs. By virtue of its selective homing for damaged endothelium, we propose that chronic administration CAR will synergize with prostacyclin and PDE5 inhibitor therapies, with greater impact on pulmonary vascular remodeling. We have devised a strategy that will optimize the dosing, formulation and delivery, pharmacokinetics and pharmacodynamics of this agent as an adjuvant therapy in combination with FDA-approved vasodilator therapies for PH. This potentially groundbreaking approach would constitute the first example of a targeted therapy specifically designed to address pulmonary vascular disease, and could address limitations of current PH therapy.

公共摘要该项目响应公告HLS16-06，描述了一个开发计划 CARSKNKDC（CAR），一种合成循环肽，有选择地靶向患病的肺血管内皮并增强血管扩张剂疗法的治疗作用，以实现治疗肺动脉高压（pH）。 pH是肺血管升高的疾病电阻以逐步增厚和抵抗性确定的遗嘱为特征肺循环的血管。尽管当前疗法，但诊断后的生存 pH值在5年时保持略高于50％，这是由于疾病进展的导致死亡率和正确的心力衰竭。作用于内皮素，前列环素和硝酸盐的血管扩张剂氧化途径适度改善功能状态，但受到全身副作用的限制，毒性和速度。没有当前的治疗选择性靶向患病的肺部循环。汽车的肽序列与蛋白肝素的序列具有高序列同源性通过噬菌体屏幕确定结合域，以增强其与脉管系统的结合软组织伤口。我们已经证明汽车在内皮中积聚，具有pH的动物而不是全身血管的肺血管中的肺血管，而不是正常动物的肺部血管。使用全身血管扩张剂疗法时，汽车增强肺血管床的选择性血管扩张，而无需增加全身性血管舒张。 CAR肽似乎可以增强药物的递送共同给药效应，而无需与药物结合。凭借其选择性归宿对于受损的内皮，我们建议长期管理汽车将与前列环蛋白和PDE5抑制剂疗法，对肺血管产生更大的影响重塑。我们制定了一种策略，可以优化给药，配方和交付，该药物的药代动力学和药效学作为辅助治疗组合使用FDA批准的血管扩张剂用于pH。这种潜在的开创性方法将构成专门针对解决的目标疗法的第一个例子肺血管疾病，可以解决当前pH疗法的局限性。