Project: Drug development platform for inflammatory diseases
Over the past few decades, scientists have realised that the process of inflammation is involved in many different diseases and that a better understanding of inflammation may lead to better treatments for numerous diseases. A comprehensive list of diseases in which inflammation is an important hallmark would run to over 100, each of which is associated with systemic and/or local inflammatory reactions. Some of these include Rheumatoid Arthritis (RA), Alzheimer's disease, asthma, irritable bowel syndrome, Parkinson's disease, sepsis and many more. While infectious diseases have been the foremost threat to public health in the last century, the current generation is faced with non-communicable diseases having a major impact on the quality of life in the developed world. Inflammatory diseases (ID) constitute a significant proportion of this issue, especially to the ageing generation. Although an increasing number of individuals are suffering from these diseases, sustained and effective medical solutions are largely unavailable. Therefore, there is a major demand for effective treatment options for the treatment of ID. Based on this medical need, the pharmaceutical industry is searching for therapeutic solutions. Many attempts have been made to target specific ID pathways however to date the vast majority of these attempts have been unsuccessful. In addition the search for effective treatment is complicated by the fact that there are no reliable animal inflammation models that can accurately mimic human inflammatory responses and predict human outcomes to test and validate newly developed drugs. As a result, the vast majority of new treatments for ID fail because of the lack of a suitable animal model. _x000D__x000D_This project will therefore focus on the construction of a drug development platform for ID. TripleA-TP aims to achieve Proof of concept (PoC) using RA as a prototypical ID. RA is a heterogeneous chronic immune mediated ID associated with significant morbidity and reduced life expectancy. The disease is common (1%) and will become more so as the population ages. Up to 10% of the European population suffers from inflammatory joint diseases which in many cases start early in life. RA is therefore a suitable condition to achieve PoC for the drug development platform._x000D__x000D_The platform will constitute of two CO pillars: 1) therapeutic access to a ubiquitous but thus far difficult to drug ID pathway 2) the development of an animal inflammation model that is more predictive of human outcomes. The therapeutic pillar will be based on ATP:adenosine modulation. Adenosine and ATP are known to have important immunomodulatory properties (Schwiebert et al., BBA 2003). Extracellular ATP (released by cells during inflammation or tissue damage) has multiple roles in inflammation and plays a major role in the activation of the immune system. Conversely, adenosine is primarily anti-inflammatory and can inhibit the production of pro-inflammatory molecules by immune cells. A recent discovery by Arthrogen showed that genes in the ATP:adenosine pathway in RA patients are differentially expressed in highly inflamed synovial tissue. RA patients appear to have a skewing of the local ATP:adenosine balance that may contribute to chronic local inflammation (fig1). In support of this finding, Arthrogen has also found a significant decrease in ATPase activity in the synovial fluid of RA patients when compared to non-RA. These data suggest that during inflammation, RA patients have increased levels of pro-inflammatory extracellular ATP and decreased levels of anti-inflammatory adenosine, thus contributing to the pathogenic inflammatory response. This new understanding of the pathophysiology of RA has led Arthrogen to investigate innovative approaches for the treatment of RA by modulating the levels of ATP and adenosine. There is evidence that this process is similarly disturbed in other ID, meaning that this approach has potentially wide reaching implications. In parallel, TripleA-TP will develop a humanised mouse inflammation model which can mimic human inflammatory responses. These mice will be able to mount a relevant inflammatory response that should more closely predict human responses in the clinic. A reliable inflammation model is currently not available but is crucial for the translation of treatments for ID to the clinic. TripleA-TP will develop a novel inflammation model that cannot only be used to examine the developed treatment strategies is this project, but will also be of great value for any other researchers working on ID. This model will improve the drug development process by more accurate examination and adjustment of novel drugs in an earlier stage. This will enhance the success rate of drugs entering clinical testing. The number of inefficient drugs that are tested in clinical trials will be reduced, thereby preventing high trial costs. This will enable industry to address the unmet medical need of ID in the near future.
|
Acronym
|
TripleA-TP
(Reference Number: 8322)
|
|
Duration
|
01/09/2013 - 31/08/2016
|
|
Project Topic
|
TripleA-TP will develop a drug development platform for inflammatory diseases, which will constitute of: 1) therapeutic access to the ubiquitous but thus far undruggable ATP:adenosine pathway 2) the development of an humanised mouse inflammation model which will be able to mimic human responses
|
|
Network
|
Eurostars
|
|
Call
|
Eurostars Cut-Off 10
|
Project partner
