# Development of Modified Caveolin-1 Scaffolding Domain Peptides with Improved Pharmacological Properties as Therapeutic Agents for Scleroderma Skin Disease

> **NIH NIH R41** · FIBROTHERAPEUTICS, INC. · 2022 · $259,601

## Abstract

Abstract 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 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). However, CSD lacks suitable pharmacologic properties for drug
development. To overcome this problem, we developed novel, modified versions of CSD. We first divided CSD
into three subregions and found that all three suppressed bleomycin-induced skin fibrosis. To improve, the
pharmacological properties, we then modified CSD and each subregion to be water soluble and protected from
proteolysis. This modification greatly enhanced the uptake by cells of all four modified peptides and also
greatly increased their ability to inhibit several purified kinases in vitro. We have so far tested only one of the
four modified peptides in vivo and it was outstandingly active in inhibiting bleomycin-induced dermal fibrosis as
well as the associated loss of the intradermal adipose layer (lipoatrophy). These initial studies justify and
outstandingly support our proposal to identify a Lead Compound from among the four candidates, then
evaluate its Therapeutic Index (ratio between toxic and beneficial doses). Our studies and the literature also
suggest 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 must
identify 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, then
demonstrate 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. Primary
Readouts will be dermal fibrosis and lipoatrophy. Secondary Readouts will be the levels of markers for
myofibroblasts, adipocytes, and inflammatory cells. Success will be defined as >50% reversal of the
deleterious effects of bleomycin and TGFβ on the Primary and Secondary Readouts. 2) Determine the
Therapeutic Index of the Lead Compound. The dose-dependence of the beneficial effects of the Lead
Compound will be determined using doses above and below our current standard dose. The toxicity of the
Lead Compound will be evaluated in a Single-Treatment Maximum Tolerated Dose (MTD) 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 sup...

## Key facts

- **NIH application ID:** 10544238
- **Project number:** 1R41AR081740-01
- **Recipient organization:** FIBROTHERAPEUTICS, INC.
- **Principal Investigator:** STANLEY R HOFFMAN
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $259,601
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544238

## Citation

> US National Institutes of Health, RePORTER application 10544238, Development of Modified Caveolin-1 Scaffolding Domain Peptides with Improved Pharmacological Properties as Therapeutic Agents for Scleroderma Skin Disease (1R41AR081740-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10544238. Licensed CC0.

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