Wound healing is a complicated biological process that includes a cascade of tightly regulated events involving different cell types and proteins. Wound healing consists of three partially overlapping phases: inflammatory, proliferative and tissue remodelling phases. Different growth factors have been tried as drugs to enhance wound healing, but these factors have often influenced only one step of the wound healing process and are therefore not very efficient healing agents. Since wound healing is a very complicated process, a regulatory molecule that activates the complete healing cascade would be a good drug candidate.
We have recently made the unique discovery that the plasma protein plasminogen is a pro-inflammatory regulator that starts up and accelerates wound healing, including the healing of chronic diabetic wounds (Shen et al., 2012). Plasminogen is a key regulatory molecule that enhances all three phases of wound healing: it potentiates the inflammatory phase by activating phagocytosis and cytokine production by macrophages, and it enhances the proliferative phase by activating non-immune cells to undergo epithelial-to-mesenchymal transition (EMT), a process which is required for the formation of granulation tissue and re-epithelization. Finally, plasminogen also participates in the remodeling of extracellular matrix. As a consequence, plasminogen activates and enhances the healing of acute as well as non-healing chronic wounds.
Wound healing is a well-orchestrated process involving migration of various cell types, such as keratinocyte, fibroblasts, and endothelial cells. Since the plasminogen activator system generates the matrix degrading protease plasmin, it has been assumed that this proteolytic system plays a major role during the later tissue remodelling phase of wound healing (dotted line in figure). However, our studies in mice have shown that the local levels of plasminogen in wounds increase dramatically during the early inflammation phase (7-folds within 24 hours) and subside during tissue formation and tissue remodelling phases. We have shown that the increased levels of plasminogen in the wounded area are caused by an increased plasminogen binding to inflammatory cells and the further transportation to the site of inflammation. Our studies have shown that, during wound healing, plasminogen enhances levels of pro-inflammatory cytokines and activates intracellular signalling and gene expression, leading to activation of inflammation and an accelerated wound healing (Shen et al., 2012).
Omnio continues to perform pre-clinical research in several other areas, in order to develop further indications.
In collaboration with the research Group at the University, Omnio investigates the specifics of the signaling systems, and the molecular pathways.
Additionally, a recombinant mammalian cell line with satisfying levels of expression yield has been developed. Omnio continues to refine this concept for potential production of large volumes of drug substance.
Patent protection has been granted for the use of Plasminogen for different treatments, primarily:
TYMPANIC MEMBRANE PERFORATION
In addition, Omnio has applied for additional patent protection for specific wound healing, and for the role of Plasminogen in reducing the wound formation in specific circumstances.
Chronic diabetic wound is an ideal first wound indication because there are so many patients that need this treatment and so far there are no active substances that can cure diabetic wounds.
Following successful clinical trials, a plasminogen based drug could help millions of patients from substantial amounts of pain and suffering, and spare the health care system resources and money.
As a lead indication, the chronic diabetic wounds also have the following characteristics:
-Convincing pre-clincial data from more than one species
-Condition is stable and well characterized
-Easy to monitor treatment results
-Well defined patient populations are available
Diabetic wounds with impaired healing are the most severe types of chronic wounds that every year affect millions of people and thereby inflict an enormous burden on the healthcare system. Currently about 350 million people have diabetes, and by 2030 the number of affected individuals is estimated to rise to about 550 millions. Approximately 15-20% of diabetic patients develop foot ulcers. Between 14% and 24% of these need to be amputated. Already now about 10-15 million diabetic patients with foot ulcers are amputated each year; this number is likely to double in the next 15-20 years. In Sweden, the cost of treating a diabetic foot ulcer is between 6 000 and 50 000 Euro, and the cost for one amputation can be as high as 100 000 Euro.
In fact, about 30% of all the costs for diabetes relate to wound care of diabetic foot ulcers in the USA. Current treatment of diabetic ulcers comprises mainly conventional wound treatment with different dressings, bandages, and antibiotics. At present, no biologically active substance that speeds up the healing of these wounds exists that is widely used on the market.
Therefore, there is a great need for future treatments in the field of wound healing, and in particular a need for pharmaceuticals for the treatment of diabetic wounds as well as other chronic wounds.
In addition to wound healing, there are several other symptoms where stimulation of the plasminogen signaling pathways has shown benefit in pre-clinical trials:
-Enhancing the host defense against infections by antibiotic resistant bacteria (Omnio patent)
-Treatment of periodontitis (Omnio patent)
-Repair of tympanic membrane (ear drum) perforation (Omnio patent)
-Repair of wounds caused by radio therapy (Omnio patent application)
-Protection from damage by radio therapy (Omnio patent application)
-Treatment of patients suffering from plasminogen deficiency (shown independently of Omnio)