Generation of a multi‐functional, target organ‐specific, anti‐fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin

Abstract

Extracellular matrix (ECM) molecules play important roles in regulating processes such as cell proliferation, migration, differentiation and survival. Decorin is a proteoglycan that binds to ('decorates') collagen fibrils in the ECM. Decorin also interacts with many growth factors and their receptors, the most notable of these interactions being its inhibitory activity on TGF-β, the growth factor responsible for fibrosis formation. We have generated a recombinant, multi-functional, fusion-protein consisting of decorin as a therapeutic domain and a vascular homing and cell-penetrating peptide as a targeting vehicle. This recombinant decorin (CAR-DCN) accumulates at the sites of the targeted disease at higher levels and, as a result, has substantially enhanced biological activity over native decorin. CAR-DCN is an example of how molecular engineering can give a compound the ability to seek out sites of disease and enhance its therapeutic potential. CAR-DCN will hopefully be used to treat severe human diseases. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…In addition, being a structural component of the ECM, DCN influences cellular functions such as proliferation, spreading, migration, differentiation and regulates inflammation [50][51][52]. DCN has received much attention as a therapeutic agent because of its anti-fibrotic, -inflammatory and -cancer effects [53][54][55]. The anti-fibrotic function of DCN is related to its property of being a natural inhibitor of TGF-β, a growth factor responsible for scarring and fibrosis [50,52,56,57].…”

Systemically Administered, Target-specific, Multi-functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…In addition to being a structural component of the ECM, DCN influences cellular functions such as proliferation, spreading, migration, differentiation and regulates inflammation [48][49][50] . DCN has received much attention as a therapeutic agent because of its anti-fibrotic, -inflammatory and -cancer effects [51][52][53] . The anti-fibrotic function of DCN is related to its property of being a natural inhibitor of TGF-β, a growth factor responsible for scarring and fibrosis [48,50,54,55] .…”

“…DCN also neutralizes CCN2 [57] , ERBBs [58][59][60] and myostatin [61,62] , an important contributor to scarring in several organs. Thus, a single DCN molecule can neutralize multiple fibrosis-inducing growth factors simultaneously as the binding sites for these growth factors exist in different parts of DCN molecule [52] .…”

“…Interestingly, a large number of naturally occurring TGF-β/bone morphogenetic protein (BMP) antagonists are also heparin binding proteins [69] . Thus, CAR peptide may have converted DCN into a selective inhibitor of scar-inducing isoforms of TGF-β through the selectivity obtained by HSPG binding [45,52] . The reengineering of the therapeutic proteins by providing them with an additional heparin binding domain could be an emerging theme in tissue engineering as a similar approach to the one used in the engineering of CAR-DCN, has been utilized more recently in generating super growth factors [8,71] .…”

Translating the matrix

“…The potential for therapeutic use of decorin to modulate cancer cell responses is reviewed in this section (Sainio and Järveläinen, ), and many of the promising preclinical data are discussed. In a second review (Järvinen and Ruoslahti, ), the use of a targeting peptide fused to decorin is discussed and its potential use in regenerative medicine reviewed. Schultz () also reviews work performed using a drug delivery system based on the latency‐associated peptide, which is secreted in complex with TGF‐β1 and acts as a protective coat for this growth factor.…”