Technology
Background
Inflammation is the body's normal response to infection, mechanical irritation, or injury. A major characteristic of the immune system is its functional redundancy: an insult triggers the synthesis and release of various proinflammatory mediators including the early lipid mediators, prostaglandins and leukotrienes. Further positive feedback loops are mediated by early infiltrating leukocytes and the release of cytokines and chemokines and lead to a full activation of both the innate and adaptive immune systems. Contrary to the common view that an inflammatory response gradually fades away is the now increasingly appreciated concept that the immune system is under the active control of homeostatic resolution pathways that are essential in limiting the inflammatory process and restoring normal tissue architecture and function. The incomplete resolution of an inflammatory response is now viewed as a significant contributor to chronic and exacerbating disease.
Recently it was discovered that a new class of mediators, the resolvins, plays a central role in the active resolution of both acute and chronic inflammatory processes. Resolvins are lipid mediators generated through the oxidation of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The important discovery is that specific oxidized mediators with unique pharmacological class differentiating properties are identified from both EPA and DHA:
It is expected that these different profiles will allow the creation of drugs with profiles targeted to different clinical indications.
While the benefit of omega-3 fatty acids in inflammatory and other diseases has long been suggested, there has been no accepted putative mechanism due to lack of molecular evidence in vitro, the high concentrations needed to show an effect in vivo, and the randomly successful clinical trials that have tried to prove a benefit for omega-3 fatty acids. The resolvins may provide the "missing" link between omega-3 fatty acids and the control of a pathological inflammatory process.
Resolvin Properties
Resolvins were first isolated in exudates formed in the resolution phase of an acute inflammation or in tissues such as the brain in response to an ischemic insult. They were then shown to be produced by human cells and were identified in human plasma. Following the breakthrough of their identification and full structural elucidation they were produced by full organic chemical synthesis to explore their pharmacological properties in various prophylactic and therapeutic disease models.
Experimental evidence to date indicates a significant potential for the EPA derived RvE1 in managing both acute and chronic inflammation with particularly strong evidence in models of colitis, periodontitis, and arthritis including profound disease modifying properties. In other experimental conditions administration of the DHA analog NPD1 prevented ischemia induced brain damage, prevented stress induced apoptosis of retinal epithelial cells, and accelerated the recovery of corneal epithelial lesions.
Resolvins meet several specific criteria that are highly desirable features of therapeutics for inflammation treatment:
- Dose-dependent actions with extremely high potencies
- Receptor specific requirements for their actions
- Combine cytokine off-switch mechanisms with activation of proresolution functions
- Highly effective in acute and chronic experimental inflammation
- Combine reduction of clinical signs of disease with powerful disease modifying properties
- Regulation without immunosuppression
The different experimental conditions used to explore the therapeutic potential of resolvins indicate that resolvins, in a coordinated and physiological fashion, modify function of several pathways in a "many-to-one" approach with a high potential for efficacy across different etiologies and pathologies.
Therapeutic advantages of resolvins
Resolvins represent a concept change from the current fashion of a highly targeted drug development approach. The current therapeutic approach for autoimmune disorders is the targeted blockade of single immune mediators such as key proinflammatory cytokines. This approach proves helpful for some indications, but significant numbers of patients still fail to respond. The functional redundancy of the immune system limits the value of single pathway elimination to achieve meaningful and sustainable clinical responses in most chronic inflammatory diseases. The resolvins "many-to-one" approach will, for the first time, address this redundancy as a major obstacle to identifying highly efficacious therapies for these diseases.
The potential clinical benefit of resolvins will not be limited to autoimmune diseases like rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The established evidence that complex immune responses participate in every phase, also the early phases, of atherosclerosis and type-2 diabetes points to the need of developing drugs that can utilize the body's own pleiotropic control of inflammation and immune system homeostasis. The predicted future huge impact of these diseases on health strongly indicates the need to develop therapies that are safe, efficacious and easy to administer to large groups of patients.
Activation of the body's own off-switch mechanisms to reestablish functional homeostasis of immune system is likely to leave intact essential functions necessary for tumor surveillance and control of infection. Resolvins will through their endogenous origin provide a unique/risk benefit offering for the treatment of chronic inflammatory conditions.
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