Our long-term objective is to develop an effective treatment for scleroderma (systemic sclerosis,SSc) skin fibrosis. Caveolin-1 is a promising therapeutic target in fibrotic diseases. The profibrotic effects ofcaveolin-1 deficiency in cells and in mouse models is suppressed by a peptide equivalent to its active site(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 that all three suppressed bleomycin-induced skin fibrosis. To improve, thepharmacological properties, we then modified CSD and each subregion to be water soluble and protected fromproteolysis. This modification greatly enhanced the uptake by cells of all four modified peptides and alsogreatly increased their ability to inhibit several purified kinases in vitro. We have so far tested only one of thefour modified peptides in vivo and it was outstandingly active in inhibiting bleomycin-induced dermal fibrosis aswell as the associated loss of the intradermal adipose layer (lipoatrophy). These initial studies justify andoutstandingly support our proposal to identify a Lead Compound from among the four candidates, thenevaluate its Therapeutic Index (ratio between toxic and beneficial doses). Our studies and the literature alsosuggest that our peptides will be more effective and have fewer side effects than the blockbuster FDA-approved drug pirfenidone (brand name Esbriet). In summary, to proceed with drug development we mustidentify a Lead Compound. Due to their distinct pharmacological and functional differences, we must do a side-by-side comparison of our four modified peptides. 1) Select a Lead Compound using two model systems:Systemic Bleomycin Treatment and Subcutaneous TGFβ Injection. We will identify a Lead Compound, thendemonstrate its specificity and activity by comparing it to a control peptide (scrambled Lead) and to nintedanib.Peptides will be delivered s.c. in a Therapeutic Protocol, beginning one week after fibrosis is induced. PrimaryReadouts will be dermal fibrosis and lipoatrophy. Secondary Readouts will be the levels of markers formyofibroblasts, adipocytes, and inflammatory cells. Success will be defined as >50% reversal of thedeleterious effects of bleomycin and TGFβ on the Primary and Secondary Readouts. 2) Determine theTherapeutic Index of the Lead Compound. The dose-dependence of the beneficial effects of the LeadCompound will be determined using doses above and below our current standard dose. The toxicity of theLead Compound will be evaluated in a Single-Treatment Maximum Tolerated Dose (MTD) Experiment using1X, 5X, 25X, and 125X our current standard dose. We will consider these studies to be a success if theTherapeutic Index is >50. In summary, these studies will provide a novel Lead Compound that meets ourCriteria for Success, both in terms of suppression of skin disease and of safety.
Public Health Relevance Statement: Narrative
Dermal fibrosis (the stiffening of the dermal layer of the skin due to collagen overproduction/deposition) and
lipoatrophy (the loss of the intradermal fat layer in the skin) are two major features of the devastating skin
disease scleroderma. 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 dermal fibrosis and lipoatrophy. In this
proposal, based on its beneficial effects in two model systems for scleroderma, 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: <22kD Caveolae Protein>
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