# Novel Therapeutics for Interstitial Lung Disease: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development

> **NIH NIH R41** · FIBROTHERAPEUTICS, INC. · 2022 · $299,930

## Abstract

Abstract Our long-term goal is to improve on the limited choices for treating the many devastating diseases
that together constitute the Interstitial Lung Diseases (ILD), the most prevalent of which are scleroderma and
Idiopathic Pulmonary Fibrosis. As ILD affects those in late middle age trying to remain active, the market for a
treatment will grow rapidly. 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 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 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 lung fibrosis. These initial studies justify and strongly
support 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 our
peptides 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. Due
to their distinct pharmacological and functional features, 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
Fluorescein Isothiocyanate (FITC) Treatment. We will choose a Lead Compound, then demonstrate its
specificity 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 be
delivered s.c. in a Therapeutic Protocol, beginning 7 days after fibrosis is induced. Primary Readouts will be
lung function and quantification of fibrosis markers, microvascular leakage, and tissue morphology. Success
will be defined as the suppression by the Lead Compound of >50% of the deleterious effect on lung function
and >75% of the deleterious effect on fibrosis and microvascular leakage. 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 cu...

## Key facts

- **NIH application ID:** 10544228
- **Project number:** 1R41HL164283-01A1
- **Recipient organization:** FIBROTHERAPEUTICS, INC.
- **Principal Investigator:** STANLEY R HOFFMAN
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $299,930
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544228

## Citation

> US National Institutes of Health, RePORTER application 10544228, Novel Therapeutics for Interstitial Lung Disease: Modified, Water-Soluble Caveolin-1 Scaffolding Domain Peptides with Improved Characteristics for Drug Development (1R41HL164283-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10544228. Licensed CC0.

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