The Use of Connexin-Based Therapeutic Approaches to Target Inflammatory Diseases

Abstract

Alterations in Connexin43 (Cx43) expression levels have been shown to play a role in inflammatory processes including skin wounding and neuroinflammation. Cx43 protein levels increase following a skin wound and can inhibit wound healing. Increased Cx43 has been observed following stroke, epilepsy, ischemia, optic nerve damage, and spinal cord injury with gap junctional communication and hemichannel opening leading to increased secondary damage via the inflammatory response. Connexin43 modulation has been identified as a potential target for protection and repair in neuroinflammation and skin wound repair. This review describes the use of a Cx43 specific antisense oligonucleotide (Cx43 AsODN) and peptide mimetics of the connexin extracellular loop domain to modulate Cx43 expression and/or function in inflammatory disorders of the skin and central nervous system. An overview of the role of connexin43 in inflammatory conditions, how antisense and peptide have allowed us to elucidate the role of Cx43 in these diseases, create models of diseases to test interventions and their potential for use clinically or in current clinical trials is presented. Antisense oligonucleotides are applied topically and have been used to improve wound healing following skin injury. They have also been used to develop ex vivo models of neuroinflammatory diseases that will allow testing of intervention strategies. The connexin mimetic peptides have shown potential in a number of neuroinflammatory disorders in ex vivo models as well as in vivo when delivered directly to the injury site or when delivered systemically.

New treatment options for hearing loss

“…Tonabersat also targets gap junctions and has been evaluated for migraine treatment 147 . Other modulators of gap junction function have been tested for applications in other areas, such as as inflammation 148 , but there are no published reports describing their use for treating hearing loss.…”

Connexin43 Mimetic Peptide Improves Retinal Function and Reduces Inflammation in a Light-Damaged Albino Rat Model

“…54 Peptide5 has previously been shown to reduce vessel leak and inflammation following central nervous system (CNS) injury, promote glial and neuronal survival, or provide improved functional outcomes in several CNS models. 24,25,28,29,55 (For a full review of hemichannel roles in CNS injury, see, e.g., Refs. 23, 25, 54, 56-59.…”

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

“…Cx43 is expressed in both epidermal and dermal cutaneous layers and has key regulatory assignments in wound repair and the processes of re-epithelialization, neovascularization, collagen deposition, and extracellular matrix remodeling (Churko et al, 2012; Cogliati et al, 2015; Ghatnekar et al, 2009; Hunter et al, 2005; Marquez-Rosado et al, 2012; Rhett et al, 2011). Hemichannels comprised of Cx43 are critical determinants of inflammatory, edematous, and fibrotic processes occurring in response to wounding, mediating purinergic signaling, and the release of proinflammatory and cytotoxic molecules (Calder et al, 2015; Lorraine et al, 2015; O’Carroll et al, 2013; Rhett et al, 2014). aCT1 is a 25-amino acid peptide designed to mimic the carboxyl terminus of Cx43 (Ghatnekar et al, 2009; Hunter et al, 2005; Rhett et al, 2011).…”