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

公开摘要 本项目是对公告HLS 16 -06的响应，描述了一个开发程序， CARSKNKDC（CAR），一种选择性靶向病变肺动脉的合成环肽 血管内皮，并增强血管扩张剂治疗的疗效， 治疗肺动脉高压（PH）。PH是一种肺血管病变， 以决定抗性的细胞逐渐增厚和消失为特征的抗性 肺循环的血管。尽管目前有治疗方法，但诊断后的生存率 5年时PH仍略高于50%，死亡率为疾病进展的结果 和右心衰竭作用于内皮素、前列环素和一氧化氮的血管扩张剂疗法 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。目前没有选择性靶向病变肺动脉的治疗方法。 流通CAR，其肽序列与蛋白肝素- 结合域，通过噬菌体筛选鉴定其与血管系统的结合增强 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， 正常动物的肺血管。当与全身性血管扩张剂治疗一起使用时，CAR 增强肺血管床的选择性血管舒张，而不增加全身 血管舒张CAR肽似乎可以通过增强药物向患病血管的递送， 共同给药效果，而不需要与药物结合。凭借其选择性归巢 对于受损的内皮，我们认为长期给予CAR将与 前列环素和PDE 5抑制剂治疗，对肺血管的影响更大 重塑我们已经设计了一种策略，将优化剂量，配方和交付， 作为联合治疗的辅助疗法的药物动力学和药效学 FDA批准的PH血管扩张剂疗法。这种潜在的突破性方法 将构成第一个专门设计用于解决 肺血管疾病，并可以解决目前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.