The Need in Chronic Inflammation
Cytokines are proteins that play a critical role in the inflammatory cascade that is part of the healing process. In response to an injury, the acute pro-inflammatory cytokine response lasts for a brief period, and afterwards, anti-inflammatory cytokines turn it off. This process of restoring the immune system to a state of balance is referred to as homeostasis. Chronic inflammatory diseases occur when the immune system is unable to return the body back to cytokine balance. The result is a continuous cycle of immune dysregulation that pushes the body further from its balanced state. Over time, chronic inflammation leads to damaged cells, tissue death, and further disease progression.
The key to treating chronic inflammation is restoring the immune system back to balance, yet current treatments for chronic inflammatory diseases are often ineffective in doing so. When systemically delivered, some current treatments can even lead to serious adverse events and widespread toxicity. Some treatments simply mask the disease symptoms, rather than addressing the root source of the inflammation. Other treatments are directed at inflammation, but they target downstream inflammatory cytokines for which there are compensatory pathways that allow disease progression. To treat inflammatory diseases in an effective, safe, long-lasting, and disease-modifying manner, patients require a therapeutic approach that addresses the master regulator of the inflammatory cascade.
IL-10: IMMUNE MODULATION BY TARGETING A MASTER REGULATOR
Enter interleukin-10 (IL-10): a master regulator of the immune response. A powerful cytokine, it plays a critical, upstream role in maintaining cytokine homeostasis across a broad range of complex chronic inflammatory diseases. IL-10 acts to modulate inflammation through multiple pathways including: suppressing transcription, translation, processing, and release of certain pro-inflammatory cytokines such as TNF-α, IL-1α, IL-1β, IL-6, IL-12, and GM-CSF; down-regulating cytokine receptors and up-regulating antagonists; and inhibiting hydrogen peroxide and nitric oxide production. IL-10 deficiency is associated with chronic inflammatory and autoimmune diseases.
CLINICALLY PROVEN NON-VIRAL PLASMID DNA DELIVERY APPROACH
Xalud Therapeutics is developing a non-viral plasmid DNA (pDNA)-delivered gene therapy that has the potential to meet the needs in chronic inflammation. Our lead therapeutic candidate, XT-150, is a locally injectable gene therapy expressing IL-10v, a proprietary modified version of IL-10. It has historically been challenging to harness the power of IL-10 in an effective therapeutic since it is rapidly cleared and attains low target concentrations. With a half-life of 2-4 hours, it would require too many repeat doses to be used effectively in the clinical setting.
To overcome these challenges, XT-150 is a naked plasmid designed to express IL-10v and has demonstrated a longer duration of effect compared to wild-type IL-10. In addition, because XT-150 uses a non-viral approach with naked pDNA, as demonstrated in over 350 patients to date, there is no concern for host integration, which can result in a stellar safety profile. In addition, there is no antibody formation, which allows for repeat dosing without waning effects. XT-150 can be injected directly into the area of chronic inflammation and supplements the body’s own IL-10 activity to better counteract the pro-inflammatory state. Xalud has made IL-10 “druggable” with large potential across inflammatory and autoimmune diseases.