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

公开摘要 本项目响应公告HLS16-06，描述了一个开发计划，用于 CARSKNKDC(CAR)，一种选择性靶向病变肺的合成环肽 血管内皮细胞和增强血管扩张剂疗法的治疗效果 治疗肺动脉高压(PH)。肺高压是一种肺血管升高性疾病 以渐进性增厚和阻值消失为特征的阻值 肺循环的血管。尽管目前有治疗方法，但确诊后的存活率 5年后，PH值保持在略好于50%的水平，死亡率是疾病进展的结果 还有右心衰竭。血管扩张剂治疗对内皮素、前列环素和一氧化氮的影响 氧化通路可以适度改善功能状态，但受到全身副作用的限制。 毒性和快速反应。目前没有选择性地针对患病的肺部疾病的治疗方法 发行量。Car，其肽序列与蛋白肝素有很高的序列同源性。 结合结构域，通过噬菌体筛选鉴定其与血管系统的增强结合 软组织伤口。我们已经证明了CAR在内皮细胞中积聚， 肺动脉高压动物的肺血管外膜，但不是全身血管，也不是 正常动物的肺血管。当给予全身血管扩张剂治疗时，护理 增强肺血管床的选择性血管扩张而不增加全身性 血管扩张。CAR多肽似乎通过以下方式增强对病变血管的药物输送 共同给药效果，不需要与药物结合。凭借其选择性寻的能力 对于受损的内皮，我们建议慢性给药CAR将与 前列环素和PDE5抑制剂治疗对肺血管影响更大 改建。我们已经制定了一项战略，将优化剂量、配方和交付， 该药联合辅助治疗的药代动力学和药效学研究 使用FDA批准的血管扩张剂治疗PH。这一潜在的开创性方法 将成为第一个专门设计用来治疗 肺血管疾病，并可解决目前PH治疗的局限性。

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.