Anti-Fibrotic Peptide

Description:

Technology: Treatment with peptide (M10) derived from mesenchymal epithelial transition factor (c-MET) demonstrates antifibrotic properties in systemic sclerosis. M10 is a ten-amino acid peptide (TRPASFWETS) derived from intracellular cytoplasmic tail of MET upon cleavage by caspase-3 enzyme. Aspartic acid residue at position 1398 of MET is essential for M10 generation. In lung fibroblasts, A549 lung cancer cells and alveolar epithelial cells expressing the D1398G variant of MET exhibit reduced auto-phosphorylation on tyrosine residues and reduced activation of Ras and MAPK, which results in an increased expression of fibrotic markers collagen and connective tissue growth factor. M10 peptide treatment in vitro decreases type I collagen levels in both scleroderma and TGFβ stimulated normal lung and skin fibroblasts (Figure 1). Molecular docking and immunoprecipitation studies identified that M10 peptide interacts with MH2 domain of Smad2 to regulate TGFβ mediated collagen synthesis. Importantly, in a bleomycin induced pulmonary fibrosis mice model where bleomycin was given 10 days prior to treatment, the M10 peptide group exhibited significantly better weight recovery, (data now shown), reduced collagen induced by bleomycin, improved lung histology and a better Ashcroft score  (Figure 2). Hence, M10 is representative of a true anti-fibrotic in vitro and in vivo, and is an attractive agent as a therapeutic treatment for pulmonary fibrosis and other fibrotic diseases.

Overview: Systemic sclerosis is a multi-system fibrotic disorder that affects skin and internal organs. Interstitial lung disease or pulmonary fibrosis is a major organ complication and a leading cause of morbidity and mortality in SSc. Hepatocyte growth factor (HGF) was identified as an antifibrotic agent that protects against tissue fibrosis and the antifibrotic effects mediated by the HGF receptor (c-MET), are impaired in lung fibroblasts isolated from subset of patients with severe SSc-ILD. Lung fibroblasts from SSc-ILD patients with poor pulmonary outcomes express the D1398G variant of the HGF receptor, and that D1398G MET receptor mutant generated in vitro does not exert any of MET’s antifibrotic effects in lung fibroblasts. In vivo administration of M10 peptide to bleomycin induced pulmonary fibrosis mice model markedly reduced fibrosis, thus providing a new avenue for treating pulmonary fibrosis patients.

Applications: Pulmonary fibrosis
Advantages: Collagen reduction, extracellular matrix protein reduction
Key Words: Pulmonary fibrosis, antifibrotic, fibroblasts, interstitial lung disease

Publications:

Akter T, et al. “Establishment of an indirect ELISA for detection of the novel antifibrotic peptide M10.”  PLos One (2017).

Atanelishvili, Ilia, et al. "M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo." Translational Research (2015).

Atanelishvili, Ilia, et al. “D1398G Variant of MET Is Associated with Impaired Signaling of Hepatocyte Growth Factor in Alveolar Epithelial Cells and Lung Fibroblasts.” PLos One (2016).

Inventors: Galina Bogatkevich, Yuichiro Shirai, & Richard Silver

Patent Status:   US 15/747,805

MUSC-FRD Technology ID: P1454

Licensing Status: This technology is currently licensed to MUSC startup, FibroBiologics. Please contact the FRD to be put in touch with Fibrobiologics.

       

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Scott Davis
Sr Licensing Manager
MUSC Foundation for Research Development
843-876-1900
davissco@musc.edu
Inventors:
Galina Bogatkevich
Yuichiro Shirai
Richard Silver
Keywords:
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