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

PUBLIC ABSTRACT This projectin response to announcement HLSdescribes a development program for CARSKNKDCCARa synthetic cyclic peptide that selectively targets diseased pulmonary vascular endothelium and enhances the therapeutic effect of vasodilator therapiesfor the treatment of pulmonary hypertensionPHPH is a disorder of elevated pulmonary vascular resistance characterized by progressive thickening and obliteration of resistance determining vessels of the pulmonary circulationDespite current therapiessurvival following the diagnosis of PH remains slightly better thanatyearswith mortality a result of disease progression and right heart failureVasodilator therapies acting upon endothelinprostacyclinand nitric oxide pathways modestly improve functional statusbut are limited by systemic side effectstoxicityand tachyphylaxisNo current therapy selectively targets the diseased pulmonary circulationCARwhose peptide sequence has high sequence homology to protein heparinbinding domainswas identified by a phage screen for its enhanced binding to the vasculature of soft tissue woundsWe have demonstrated that CAR accumulates in the endothelium and adventitia of pulmonary vessels in animals with PHbut not systemic vesselsand not the pulmonary vessels of normal animalsWhen given with systemic vasodilator therapiesCAR potentiates selective vasodilatation of the pulmonary vascular bed without increasing systemic vasodilationCAR peptide appears to enhance the delivery of drugs to diseased vessels by a co administration effect without requiring conjugation to drugsBy virtue of its selective homing for damaged endotheliumwe propose that chronic administration CAR will synergize with prostacyclin and PDEinhibitor therapieswith greater impact on pulmonary vascular remodelingWe have devised a strategy that will optimize the dosingformulation and deliverypharmacokinetics and pharmacodynamics of this agent as an adjuvant therapy in combination with FDA approved vasodilator therapies for PHThis potentially groundbreaking approach would constitute the first example of a targeted therapy specifically designed to address pulmonary vascular diseaseand could address limitations of current PH therapy Project Narrative Pulmonary hypertension describes a diverse set of diseases characterized by elevated pressures and progressive obstruction of the lung vessels with a survival of approximatelyyears following diagnosis despite current treatmentsCurrent therapies are vasodilators that are not specific for lung vesselsand are limited in their use by their tendency to lower pressure in all blood vessels and cause side effects or toxicity in other organsThe current proposal examines a new type of drug molecule which targets only diseased lung blood vessels and which may improve the efficacy and reduce side effects of current treatments by concentrating their effects in diseased lung vessels