Gap junctions are a class of transmembrane channel proteins that occur in all cells in the body and allow adjacent cells in animal tissues to communicate with one another. They normally enable small molecules up to ~1000 Daltons and simple ions to flow between adjacent cells in a controlled manner. The six proteins that covalently bind to form gap junctions are called connexins. Six connexin proteins form a hemichannel which is a donut shaped hexagonal arrangement with a central channel which enters the cell membrane as a closed non-functional pore. This structure can migrate around the cell membrane until its extracellular protein loops “dock” to an analogous hemichannel structure on a neighboring cell to form the gap junction channel. This then establishes a direct communication channel between cells. In the normal state, gap junction hemichannels (GJHs) are closed and do not open until they dock with the GJH on an adjacent cell to allow cell-to-cell communication.
In the presence of pathological stimuli such as acute injury or chronic disease, the hemichannels open and release ATP into the extracellular milieu. The released ATP activates an inflammatory response which is mediated by the innate inflammasome pathway of inflammation. Simultaneously there is an upregulation of Connexin43 which is then overexpressed further adding to the number of open gap junction hemichannels and creating a perpetuated cycle of inflammation. This cycle continues to cause the release of ATP and inflammatory cytokines leading to significant tissue damage including microvascular leak, edema, microvascular dropout, ischemia and ultimately fibrosis.
The purpose of OcuNexus drug treatment is to break the cycle of activated inflammasome mediated inflammation by inhibiting the overexpressed Connexin43 protein. This will either prevent pathological open hemichannels from being formed or close the hemichannels directly, returning them to a state of homeostasis.
Once the cycle of inflammation is eliminated the damaged tissue has the opportunity to begin a regenerative process. This provides the potential for elimination of the need for chronic dosing to an “as needed” dosing schedule, based on tissue and clinical response of the patient.
Key Bullet Points:
- Three proprietary connexin hemichannel modulators (Nexagon®, Peptagon™ and HCB1019) with distinct modes of action offer potential for topical, systemic, intravitreal and oral administration opportunities.
- A clearly defined and proven method of treatment targeting the inflammasome pathway and endothelial cell loss in acute and chronic disease conditions, representing a paradigm shift in our understanding and regulation of these pathways.
- Upstream targeting to prevent onset and perpetuation of the inflammasome cycle and its downstream effects.
- Significantly reducing inflammation, vascular leak edema, and fibrosis (leading to improved wound healing) proven in multiple animal models and across multiple tissue types.
- World leading connexin channel modulation experience backed up with over 15 years of research and over 60 peer reviewed publications on gap junction channel modulation.
- Efficacy shown in internationally accepted ocular models including models of diabetic retinopathy and dry age-related macular degeneration.
- Efficacy established in human indications: the mechanism has been clinically demonstrated in the anterior segment of the eye with the compassionate use of Nexagon®.
- Highly experienced management and clinical development team, with research from one of the world’s leading gap junction research laboratories who produced a wider range of in vivo model data than any other group in the field.
- Over thirty patent families.
- Data generated in the laboratories of Professor Colin Green (University of Auckland, New Zealand) and Professor David Becker (Nanyang Technical University, Singapore).
- The underlying fundamental modulation technology has been shown to work in a variety of tissue types including, eye, skin, brain, nerve, and spinal cord.