A Multicenter Randomized Controlled Trial Evaluating a Cx43-Mimetic Peptide in Cutaneous Scarring

Abstract

The transmembrane protein Cx43 has key roles in fibrogenic processes including inflammatory signaling and extracellular matrix composition. aCT1 is a Cx43 mimetic peptide that in preclinical studies accelerated wound closure, decreased inflammation and granulation tissue area, and normalized mechanical properties after cutaneous injury. We evaluated the efficacy and safety of aCT1 in the reduction of scar formation in human incisional wounds. In a prospective, multicenter, within-participant controlled trial, patients with bilateral incisional wounds (≥10 mm) after laparoscopic surgery were randomized to receive acute treatment (immediately after wounding and 24 hours later) with an aCT1 gel formulation plus conventional standard of care protocols, involving moisture-retentive occlusive dressing, or standard of care alone. The primary efficacy endpoint was average scarring score using visual analog scales evaluating incision appearance and healing progress over 9 months. There was no significant difference in scar appearance between aCT1- or control-treated incisions after 1 month. At month 9, aCT1-treated incisions showed a 47% improvement in scar scores over controls (Vancouver Scar Scale; P = 0.0045), a significantly higher Global Assessment Scale score (P = 0.0009), and improvements in scar pigmentation, thickness, surface roughness, and mechanical suppleness. Adverse events were similar in both groups. aCT1 has potential to improve scarring outcome after surgery.

The Connexin 43 Carboxyl Terminal Mimetic Peptide αCT1 Prompts Differentiation of a Collagen Scar Matrix Resembling Unwounded Skin

“…8,15,29,30 Consistent with preclinical observations, a Phase II clinical trial determined that αCT1 improved scar visual appearance by 47% 9 months post-surgery relative to within-patient controls following laparoscopic surgery. 31 This long-term improvement showed a trend of progressive emergence over the study period, with a modest 12.9 % augmentation over control observed at 3 months, but no apparent difference between αCT1 and control scars at 1 month. In the present study, we took advantage of an earlier vehicle-controlled Phase I clinical trial evaluating the safety and tolerability of αCT1 involving 49 healthy subjects in which scar tissue was biopsied from the wound site 29 days following cutaneous injury.…”

Targeting the Cx43 Carboxyl Terminal H2 Domain Preserves Left Ventricular Function Following Ischemia-Reperfusion Injury

“…The biochemical characterizations indicated that αCT1 is capable of two distinct protein-protein interactions -one with ZO-1 PDZ2 and the other with the Cx43 H2 region. This raised the question as to whether or not the previously characterized effects of αCT1 in cardiac injury models 11,12 , or indeed its wound healing effects at large [16][17][18]24 , could be accounted for by one or another of these protein-protein interactions. The series of αCT1-based variant peptides generated for the present study provided an opportunity to address this question.…”

“…The details of αCT1 molecular mechanism is of key translational significance as this therapeutic peptide is presently the subject of testing in the clinic 15 . In Phase II clinical trials, αCT1 showed efficacy in promoting the healing of two types of chronic, slow healing skin wounds [16][17][18] . αCT1 is currently in Phase III testing on more than 500 patients, as a treatment for diabetic foot ulcers (GAIT1 trial) 19 .…”

Review: Multimodal bioactive material approaches for wound healing

“…61 While the exact mechanism of action remains unknown, Cx43 has been known to a regulate transforming growth factor beta (TGF-b) signaling, a marker of fibrosis. 61 Early human trials saw relative success of the material in reducing scar formation following surgery 62 and healing diabetic foot ulcers. 63 Phase 3 clinical trials are ongoing to evaluate the efficacy of this material in diabetic chronic foot ulcers.…”