Exposed CendR Domain in Homing Peptide Yields Skin-Targeted Therapeutic in Epidermolysis Bullosa

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Pemmari , T , Ivanova , L , May , U , Lingasamy , P , Tobi , A , Pasternack , A , Prince , S , Ritvos , O , Makkapati , S , Teesalu , T , Cairo , M S , Järvinen , T A H & Liao , Y 2020 , ' Exposed CendR Domain in Homing Peptide Yields Skin-Targeted Therapeutic in Epidermolysis Bullosa ' , Molecular therapy , vol. 28 , no. 8 , pp. 1833-1845 . https://doi.org/10.1016/j.ymthe.2020.05.017

Title: Exposed CendR Domain in Homing Peptide Yields Skin-Targeted Therapeutic in Epidermolysis Bullosa
Author: Pemmari, Toini; Ivanova, Larisa; May, Ulrike; Lingasamy, Prakash; Tobi, Allan; Pasternack, Anja; Prince, Stuart; Ritvos, Olli; Makkapati, Shreya; Teesalu, Tambet; Cairo, Mitchell S.; Järvinen, Tero A. H.; Liao, Yanling
Contributor: University of Helsinki, Department of Physiology
University of Helsinki, Department of Physiology
Date: 2020-08-05
Number of pages: 13
Belongs to series: Molecular therapy
ISSN: 1525-0016
URI: http://hdl.handle.net/10138/319393
Abstract: Systemic skin-selective therapeutics would be a major advancement in the treatment of diseases affecting the entire skin, such as recessive dystrophic epidermolysis bullosa (RDEB), which is caused by mutations in the COL7A1 gene and manifests in transforming growth factor-beta (TGF-beta)-driven fibrosis and malignant transformation. Homing peptides containing a C-terminal R/KXXR/K motif (C-end rule [CendR] sequence) activate an extravasation and tissue penetration pathway for tumor-specific drug delivery. We have previously described a homing peptide CRKDKC (CRK) that contains a cryptic CendR motif and homes to angiogenic blood vessels in wounds and tumors, but it cannot penetrate cells or tissues. In this study, we demonstrate that removal of the cysteine from CRK to expose the CendR sequence confers the peptide novel ability to home to normal skin. Fusion of the truncated CRK (tCRK) peptide to the C terminus of an extracellular matrix protein de-corin (DCN), a natural TGF-beta inhibitor, resulted in a skin-homing therapeutic molecule (DCN-tCRK). Systemic DCN-tCRK administration in RDEB mice led to inhibition of TGF-beta signaling in the skin and significant improvement in the survival of RDEB mice. These results suggest that DCN-tCRK has the potential to be utilized as a novel therapeutic compound for the treatment of dermatological diseases such as RDEB.
Subject: TISSUE GROWTH-FACTOR
COLLAGEN GENE COL7A1
FACTOR-BETA
FIBROBLAST PROLIFERATION
DECORIN
NANOPARTICLES
CELL
RECEPTOR
DISEASE
PROTEOGLYCANS
3111 Biomedicine
11832 Microbiology and virology
1184 Genetics, developmental biology, physiology
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