Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-ß (TGFß) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology.
Pharmaceutics
; 13(9)2021 Sep 18.
Article
em En
| MEDLINE
| ID: mdl-34575582
ABSTRACT
Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-ß1 (TGFß1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFß1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFß1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFß1 signaling by the targeted delivery of therapeutic decorin (a natural TGFß 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 TGFß1 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Pharmaceutics
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos