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：
9789689
负责人：
PAUL B YU
金额：
$ 74.61万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789689
关键词：
Acute Address Adjuvant Adjuvant Therapy Animals 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 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 pharmacokinetics and pharmacodynamics pressure protein aminoacid sequence response side effect 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 HLS16-06 公告，描述了一个开发计划 CARSKNKDC (CAR)，一种合成环肽，选择性靶向患病肺部血管内皮细胞并增强血管扩张剂疗法的治疗效果，治疗肺动脉高压（PH）。 PH 是一种肺血管升高的疾病阻力的特征是阻力决定性的逐渐增厚和消失肺循环的血管。尽管目前有治疗方法，但诊断后的生存率 5 年后 PH 的比率仍略高于 50%，死亡率是疾病进展的结果和右心衰竭。作用于内皮素、前列环素和硝酸的血管扩张剂疗法氧化物途径适度改善功能状态，但受到全身副作用的限制，毒性和快速耐受性。目前尚无选择性针对患病肺部的治疗方法循环。 CAR，其肽序列与蛋白肝素具有高度序列同源性结合域，通过噬菌体筛选鉴定出其与脉管系统的结合增强软组织伤口。我们已经证明 CAR 在内皮细胞中积累 PH 动物的肺血管外膜，但不是全身血管，也不是正常动物的肺血管。当与全身性血管扩张剂联合治疗时，CAR 增强肺血管床的选择性血管舒张而不增加全身性血管舒张。 CAR 肽似乎可以通过以下方式增强药物向患病血管的输送：无需与药物结合即可产生共同给药效果。凭借其选择性归航对于受损的内皮，我们建议长期施用 CAR 将与前列环素和PDE5抑制剂治疗，对肺血管影响更大重塑。我们制定了一项策略来优化剂量、配方和交付，该药物联合辅助治疗的药代动力学和药效学使用 FDA 批准的血管扩张剂治疗 PH。这种潜在的突破性方法将构成专门设计用于解决问题的靶向治疗的第一个例子肺血管疾病，并可以解决当前 PH 治疗的局限性。