Connexin 43-Based Therapeutics for Dermal Wound Healing

Abstract

The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (αCT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on αCT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body’s natural healing response for improved patient outcomes across a variety of injuries.

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

“…Immediately following injury, hemostasis is initiated and involves the accumulation of clotting factors to prevent bleeding. Next, blood vessels enable the invasion of inflammatory leukocytes through dilation and increased permeability, resulting in phagocytosis of exogenous bacteria and damaged cells [52]. The restoration of the epithelium then proceeds by the release of several growth factors, such as epidermal growth factor (EGF) and fibroblast growth factor (FGF).…”

“…For example, the A-connexin carboxyl-terminal peptide (ACT-1) can accomplish that by targeting the carboxy tail of Cx43. This prevents any interaction with ZO-1 and results in increased gap junction plaque size [46,55] by competitively inhibiting the interaction between the PDZ binding domains on both proteins [52]. Notably, ACT-1 does not interfere with expression levels, suggesting the role it plays in wound healing is not likely to be facilitated by Cx43 expression.…”

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

“…[5][6][7] Connexin 43 (Cx43) is a transmembrane channel protein that is expressed in both the epidermal and dermal layers of the skin, which has been shown to have key assignments in the dermal injury response. [8][9][10][11][12][13][14][15][16] Regulated reduction of Cx43 expression in wounded skin is essential for normal wound healing, 17 with Cx43 levels being dysregulated and overexpressed in chronic non-healing wounds. 18,19 Genetically reducing the overall level of Cx43 in normal mice resulted in accelerated wound reepithelialization and wound closure, increased dermal fibroblast activity, and enhanced expression of extracellular matrix (ECM) remodeling factors.…”

“…14 Alpha Connexin Carboxy-Terminus 1 (αCT1) is a peptide mimic of the Carboxyl Terminus (CT) of Cx43, encompassing a class II PSD95/Dlg/ZO-1 (PDZ) binding motif that interacts with the PDZ 2 domain of Zonula Occludens-1 (ZO-1). 8,15,22,23 In addition to interaction with ZO-1 PDZ2, αCT1 has been shown to directly interact with the H2 domain of Cx43. 24 Mouse cardiac injury models have indicated this interaction prompts phosphorylation of a serine at position 368 on Cx43 -a posttranslational modification linked to reduced activity of Cx43-formed membrane channels.…”

Targeting Cx26 Expression by Sustained Release of Cx26 Antisense from Scaffolds Reduces Inflammation and Improves Wound Healing

“…It is now well established that the gap junction protein connexin 43 (Cx43) plays a central role in the wound healing process . Indeed, targeting Cx43 with either antisense or mimetic peptides is able to promote acute wound healing and kick start healing in chronic wounds in man . In normal acute wound healing, Cx43 is naturally downregulated in wound edge keratinocytes and fibroblasts (but remains high in the proliferative cells behind the healing wound edge).…”