Project Grant R41HL167327

NOVEL THERAPEUTICS FOR HEART FAILURE: MODIFIED, WATER-SOLUBLE CAVEOLIN-1 SCAFFOLDING DOMAIN PEPTIDES WITH IMPROVED CHARACTERISTICS FOR DRUG DEVELOPMENT - ABSTRACT OUR LONG-TERM OBJECTIVE IS TO FILL THE UNMET NEED FOR TREATMENTS FOR HEART FAILURE (HF). CAVEOLIN-1 IS A PROMISING THERAPEUTIC TARGET IN FIBROTIC DISEASES. THE PROFIBROTIC EFFECTS OF CAVEOLIN-1 DEFICIENCY IN CELLS AND IN MOUSE MODELS IS SUPPRESSED BY A PEPTIDE EQUIVALENT TO ITS ACTIVE SITE (CAVEOLIN-1 SCAFFOLDING DOMAIN, CSD). WE HAVE SHOWN THE BENEFICIAL EFFECTS OF CSD IN TWO INDEPENDENT MODELS OF PO-INDUCED CARDIAC DISEASE [TRANSVERSE AORTIC CONSTRICTION (TAC) AND ANGIOTENSIN II (ANGII) INFUSION] AND ALSO IN AGED MICE. IN ALL THESE MODELS, CSD ALMOST COMPLETELY SUPPRESSED PATHOLOGICAL ALTERATIONS IN VENTRICULAR FUNCTION, FIBROSIS, AND MICROVASCULAR LEAKAGE. HOWEVER, CSD LACKS SUITABLE PHARMACOLOGIC PROPERTIES FOR DRUG DEVELOPMENT. TO ADDRESS THIS ISSUE, WE DEVELOPED NOVEL, MODIFIED VERSIONS OF CSD. WE FIRST DIVIDED CSD INTO THREE SUBREGIONS (AMINO ACIDS 82- 89, 88-95, 94-101) AND FOUND THEY ALL SUPPRESSED FIBROTIC DISEASE IN VIVO. TO IMPROVE THEIR PHARMACOLOGY, WE MODIFIED CSD AND EACH SUBREGION TO BE WATER SOLUBLE AND PROTECTED FROM PROTEOLYSIS. THIS MODIFICATION ALSO ENHANCED THEIR UPTAKE BY CELLS AND INCREASED THEIR ABILITY TO INHIBIT SEVERAL PURIFIED KINASES IN VITRO. SO FAR, WE HAVE ONLY HAD THE OPPORTUNITY TO TEST THE MODIFIED, WATER-SOLUBLE VERSION OF 82-89 (W82-89) IN AN HF MODEL. W82-89 WOULD BE AN EXCELLENT LEAD COMPOUND BASED ON ITS EFFECTS ON CARDIAC HYPERTROPHY, FIBROSIS, AND MICROVASCULAR LEAKAGE. HOWEVER, BECAUSE OF THE DISTINCT PHARMACOLOGICAL PROPERTIES OF OUR FOUR MODIFIED PEPTIDES, IT IS QUITE POSSIBLE THAT ANOTHER PEPTIDE IS MORE EFFECTIVE THAN W82-89. THUS, TO SELECT A LEAD COMPOUND, WE WILL PERFORM A SIDE-BY-SIDE COMPARISON OF THE FOUR CANDIDATES. WE WILL THEN DETERMINE THE THERAPEUTIC INDEX (RATIO BETWEEN TOXIC AND BENEFICIAL DOSES) OF THE LEAD COMPOUND. SPECIFICALLY, WE WILL: 1) SELECT A LEAD COMPOUND USING TWO MODEL SYSTEMS: ANGII- AND ISOPROTERENOL-INDUCED HF. ANGII AND ISOPROTER- ENOL INFUSION ARE TWO FREQUENTLY USED, MECHANISTICALLY DISTINCT, MODEL SYSTEMS FOR INDUCING HF IN MICE. STUDIES WILL BE PERFORMED BOTH IN A PROPHYLACTIC AND IN A THERAPEUTIC FORMAT (I.E. TREATMENT BEGINS ONLY AFTER DISEASE IS ESTABLISHED). WE WILL CONSIDER THESE STUDIES TO BE A SUCCESS IF A LEAD COMPOUND IS SELECTED THAT SUPPRESSES THE PATHOLOGICAL EFFECTS OF ANGII AND ISOPROTERENOL ON VENTRICULAR FUNCTION (EJECTION FRACTION [EF], FRACTIONAL SHORTENING [FS], ISOVOLUMIC RELAXATION TIME [IVRT]) AND CARDIAC HYPERTROPHY [HEART WEIGHT/BODY WEIGHT RATIO] BY >50% AND THE EFFECTS ON FIBROSIS AND MICROVASCULAR LEAKAGE BY >75%. 2) DETERMINE THE THERAPEUTIC INDEX OF THE LEAD COMPOUND. THE DOSE-DEPENDENCE OF THE LEAD COMPOUND'S BENEFICIAL EFFECTS WILL BE DETERMINED USING DOSES ABOVE AND BELOW OUR CURRENT STANDARD DOSE. ITS TOXICITY WILL BE EVALUATED IN A SINGLE-TREATMENT MAXIMUM TOLERATED DOSE EXPERIMENT USING 1X, 5X, 25X, AND 125X OUR CURRENT STANDARD DOSE. WE WILL CONSIDER THESE STUDIES TO BE A SUCCESS IF THE THERAPEUTIC INDEX IS >50. IN SUMMARY, THESE STUDIES WILL PROVIDE A NOVEL LEAD COMPOUND THAT MEETS OUR CRITERIA FOR SUCCESS, BOTH IN TERMS OF SUPPRESSION OF HF AND OF SAFETY.