Our long-term goal is to improve on the limited choices for treating the many devastating diseasesthat together constitute the Interstitial Lung Diseases (ILD), the most prevalent of which are scleroderma andIdiopathic Pulmonary Fibrosis. As ILD affects those in late middle age trying to remain active, the market for atreatment will grow rapidly. Caveolin-1 is a promising therapeutic target in fibrotic diseases. The profibroticeffects of caveolin-1 deficiency in cells and in mouse models is suppressed by a peptide equivalent to its activesite (caveolin-1 scaffolding domain, CSD). However, CSD lacks suitable pharmacologic properties for drugdevelopment. To overcome this problem, we developed novel, modified versions of CSD. We first divided CSDinto three subregions and found they all suppressed bleomycin-induced lung fibrosis. To improve the pharma-cological properties, we then modified CSD and each subregion to be water soluble and protected from proteo-lysis. This modification enhanced the uptake by cells of all four modified peptides and increased their ability toinhibit several purified kinases in vitro. We have so far tested only one of the four modified peptides in vivo andit was outstandingly active in inhibiting bleomycin-induced lung fibrosis. These initial studies justify and stronglysupport our proposal to identify a Lead Compound from among the four candidates, then evaluate its Thera-peutic Index (ratio between toxic and beneficial doses). Our studies and the literature also suggest that ourpeptides will be more effective and have fewer side effects than the FDA-approved blockbuster drug nintedanib(brand name Ofev). In summary, to proceed with drug development we must identify a Lead Compound. Dueto their distinct pharmacological and functional features, we must do a side-by-side comparison of our fourmodified peptides. 1) Select a Lead Compound using two model systems: Systemic Bleomycin Treatment andFluorescein Isothiocyanate (FITC) Treatment. We will choose a Lead Compound, then demonstrate itsspecificity and activity by comparing it to a control peptide (scrambled Lead), nintedanib, and pirfenidone(brand name Esbriet, an FDA-approved drug for ILD reported to affect caveolin-1 levels). Peptides will bedelivered s.c. in a Therapeutic Protocol, beginning 7 days after fibrosis is induced. Primary Readouts will belung function and quantification of fibrosis markers, microvascular leakage, and tissue morphology. Successwill be defined as the suppression by the Lead Compound of >50% of the deleterious effect on lung functionand >75% of the deleterious effect on fibrosis and microvascular leakage. 2) Determine the Therapeutic Indexof the 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 ILD 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 lung function that occur in the group of devastating diseases known as the
Interstitial Lung Diseases (ILD). 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 in multiple model systems. In this proposal, based on its beneficial effects in two model
systems for ILD, we will select a Lead Compound for further development 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: <5-Isothiocyanatofluorescein><22kD Caveolae Protein>
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