Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology.

Aqsa Iqbal,Ahlke Heydemann,Ulrike May,Tero A.H. Järvinen,Stuart N. Prince

doi:10.3390/pharmaceutics13091506

Abstract

Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy.

Highlights

Muscular dystrophies (MD) are the most prevalent genetic diseases in the world [1].MDs are comprised of over 20 different genetic disorders, which result in progressive breakdown of skeletal muscle
Recent research has shown that it targets damaged vasculature in inflammatory diseases [17,18,19]. This prompted us to explore whether CAR peptide could home to dystrophic lesions in mouse models of muscular dystrophy
The fluorescein isothiocyanate (FITC)-tag from the chimeric protein co-localized with Evans blue dye (EBD) positive fibers in mdxD2 mice (Figure 1)

Summary

Introduction

MDs are comprised of over 20 different genetic disorders, which result in progressive breakdown of skeletal muscle. They are characterized by membrane permeability, immune infiltration, myofiber necrosis, repeated rounds of degeneration and regeneration, eventual failure of the regeneration process, myofibroblast replacement of muscle tissue, and, functionally impeding fibrosis [2,3]. Among the large numbers of different MDs, the most prevalent and one of the most severe is Duchenne MD (DMD), which can be modeled by mdx-mice. TGFβ1 is pathologically upregulated in human and murine MD [5]. TGFβ1 inhibition reduces murine MD-mediated fibrosis and immune system-mediated pathogenesis [6]. TGFβ1 inhibition reduces murine MD-mediated fibrosis and immune system-mediated pathogenesis [6]. mdx mice treated with TGFβ1 neutralizing antibody for six weeks had reduced

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Discussion

Conclusion