HLS Cyclic CAR peptide a targeted therapy for pulmonary hypertension

PUBLIC ABSTRACT This project in response to announcement HLS 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 at 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 PDE 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 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 approximately years following diagnosis despite current treatments Current therapies are vasodilators that are not specific for lung vessels and are limited in their use by their tendency to lower pressure in all blood vessels and cause side effects or toxicity in other organs The 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