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.
Public Health Relevance Statement: 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 5 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.
Project Terms: Acute; Address; Adjuvant; Adjuvant Therapy; Adverse effects; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Bacteriophages; base; Binding; Bioavailable; Biological Assay; Biological Availability; Blood Vessels; cationic antimicrobial protein CAP 37; Chronic; Combination Drug Therapy; Combined Modality Therapy; Cyclic Peptides; design; Diagnosis; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Kinetics; efficacy testing; Endothelin; Endothelin Receptor Antagonist; Endothelium; Exhibits; FDA approved; Formulation; functional status; Heart failure; hemodynamics; Homing; Hypoxia; Immunoassay; improved; inhibitor/antagonist; intravenous administration; Lung; Lung diseases; Mass Spectrum Analysis; Modeling; Monocrotaline; mortality; nanoparticle; Nitric Oxide Pathway; novel therapeutics; Obstruction; Oral; Oral Administration; Organ; Peptides; Periodicity; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology Study; Pharmacotherapy; Phase; Physiological; pressure; Program Development; Prostaglandins I; protein aminoacid sequence; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary vessels; Rattus; Resistance; response; Right Ventricular Hypertrophy; Safety; Sensitivity and Specificity; Sequence Homology; Serum; sildenafil; soft tissue; Sublingual drug administration; synergism; System; Tachyphylaxis; targeted treatment; Therapeutic Effect; Toxic effect; tumor; Tumor Tissue; Tunica Adventitia; vascular bed; Vascular Diseases; Vascular Endothelium; Vascular remodeling; Vasodilation; Vasodilator Agents; Ventricular
