Our long-term objective is to fill the unmet need for treatments for heart failure (HF). Caveolin-1 is a promisingtherapeutic target in fibrotic diseases. The profibrotic effects of caveolin-1 deficiency in cells and in mousemodels is suppressed by a peptide equivalent to its active site (caveolin-1 scaffolding domain, CSD). We haveshown the beneficial effects of CSD in two independent models of PO-induced cardiac disease [transverseaortic constriction (TAC) and angiotensin II (AngII) infusion] and also in aged mice. In all these models, CSDalmost completely suppressed pathological alterations in ventricular function, fibrosis, and microvascularleakage. 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, wemodified CSD and each subregion to be water soluble and protected from proteolysis. This modification alsoenhanced their uptake by cells and increased their ability to inhibit several purified kinases in vitro. So far, wehave 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, andmicrovascular leakage. However, because of the distinct pharmacological properties of our four modifiedpeptides, it is quite possible that another peptide is more effective than W82-89. Thus, to select a LeadCompound, we will perform a side-by-side comparison of the four candidates. We will then determine theTherapeutic 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. Studieswill be performed both in a prophylactic and in a therapeutic format (i.e. treatment begins only after disease isestablished). We will consider these studies to be a success if a Lead Compound is selected that suppressesthe pathological effects of AngII and isoproterenol on ventricular function (Ejection Fraction [EF], fractionalshortening [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 ofthe Lead Compound. The dose-dependence of the Lead Compound's beneficial effects will be determinedusing doses above and below our current standard dose. Its toxicity will be evaluated in a Single-TreatmentMaximum Tolerated Dose Experiment using 1X, 5X, 25X, and 125X our current standard dose. We willconsider these studies to be a success if the Therapeutic Index is >50. In summary, these studies will providea novel Lead Compound that meets our Criteria for Success, both in terms of suppression of HF and of safety.
Public Health Relevance Statement: Narrative
Fibrosis (the stiffening of tissues due to collagen overproduction/deposition) and blood vessel leakage are
major contributors to the deficits in ventricular function that occur in Heart Failure (HF). We have been working
on novel, modified versions suitable for drug development of a biologic peptide (called CSD) that we have
already shown to suppress fibrosis and blood vessel leakage and to improve ventricular function in multiple
model systems for HF. In this proposal, based on its beneficial effects in two model systems, we will select a
Lead Compound for further development as a treatment for HF from among four candidates that we have
designed and, additionally, we will evaluate the potential toxicity of this Lead Compound in a Maximum
Tolerated Dose experiment.
Project Terms: <21+ years old><7S Gamma Globulin> |
