Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice

Abstract

Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.

Tendon Healing: Repair and Regeneration

“…On the one hand, biological augmentations of IGF-1 can improve tendon healing, and the absence of IGF-1 leads to an inferior repair response. On the other hand, reductions in levels of TGFβ have been associated with reduced scar formation (111).…”

The wound healing, chronic fibrosis, and cancer progression triad

“…Animal models have shown that absence of decorin exacerbates fibrosis (13, 247, 316). Moreover, interesting data suggest that decorin itself could be a beneficial Review antifibrotic therapeutic alternative (156,186,402). A suggested antifibrotic mechanism of decorin deals, at least partially, with the inactivation of TGF-␤ signaling (14), impairing myofibroblastic differentiation in liver fibrosis models (14).…”

Collagen VII plays a dual role in wound healing

“…Most importantly, loss of COL7A1 led to increased production of TGF-β1, which stimulates synthesis of extracellular matrix and scarring in RDEB (43)(44)(45). TGF-β signaling and tissue stiffness drive myofibroblast differentiation (46)(47)(48).…”