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Interdisciplinary training network on the purinergic P2X7 receptor to control neuroinflammation and hyperexcitability in brain diseases.

Periodic Reporting for period 2 - PurinesDX (Interdisciplinary training network on the purinergic P2X7 receptor to control neuroinflammation and hyperexcitability in brain diseases.)

Reporting period: 2019-09-01 to 2021-08-31

Brain disorders affect ~179 million people and their families in Europe alone, with an annual cost to the taxpayer estimated at €800 billion- a greater economic burden than cardiovascular disease and cancer combined. Despite diverse etiology, overlap in clinical symptoms and comorbidities between brain disorders suggests shared pathomechanisms. In particular, increased hyperexcitability states in the brain driven by glial activation and neuroinflammation appear near ubiquitous. Accordingly, targeting these mechanisms may offer the potential to ameliorate symptoms and reverse disease progression across a broad span of brain disorders. Functioning as a gatekeeper to neuroinflammation and mechanistic link between neuronal hyperexcitability and glial activation, the ATP-gated, ionotropic purinergic P2X7 receptor (P2X7R) offers the most promising target for pharmacological intervention in the neuroinflammation-hyperexcitability pathway, to date. With breakthroughs in understanding P2X7R function, highly promising effects demonstrated for antagonists in models of brain disease and vast investment in P2X7R-related drug development programmes, now is the perfect time to pool resources.
PurinesDX brings together global leaders in translational research in purinergic signalling, Europe’s leading clinical specialists in a broad range of brain diseases, and industrial partners specializing in drug and biomarker development. Sharing unique genetic tools, newly developed diagnostic devices and novel, selective and brain-stable P2X7R antagonists, the synergism facilitated within PurinesDX will extend to the training of an urgently needed new generation of highly skilled, innovative, creative and entrepreneurial scientists. Alongside the provision of this interdisciplinary, international and intersectoral environment, an original and high level training in state-of-the-art neuroscience will be provided, nurturing a cohort of highly competitive researchers with potential to drive a new era of neuroscience research.
The specific PurinesDX aims are:
(i) Determine P2X7R function and cellular and sub-cellular expression across brain diseases (WP1)
(ii) Establish the cell-specific effects of increased P2X7R activity on disease pathology and determine the impact of pharmacological targeting of P2X7R on disease progression in diseases of the brain (WP2)
(iii) Identify P2X7R signature and purine metabolites as disease risk and biomarker-based diagnostics of brain diseases (WP3)
PurinesDX research activities are grouped into three work packages (Work Packages 1-3). In WP1, P2X7 expression and function has now been analysed in an array of brain diseases and data for Alzheimer’s disease has recently been published (Martínez-Frailes C et al. (2019) Front Cell Neurosci 13:143). In addition, evidence of P2X7 altered function during brain disease has also been established (e.g. novel splice variants during Huntington’s disease).
In WP2, data from the consortium shows the potential of P2X7 as a drug target for the treatment of brain diseases, specifically in Amyotrophic Lateral Sclerosis (ALS) and drug-refractory epilepsy. In WP3, good progress has also been made in establishing potential new diagnostic tools based on P2X7 down-stream signalling including blood purines and inflammatory markers such as P2X7-dependent cytokines
In parallel with the research developed by PurinesDX ESRs, a tailored training programme was implemented, covering basic, transferable and specific skills relevant to the research fields addressed in PurinesDX. Eight network-wide courses have been organised with a comprehensive range of theory and hands-on technical workshops to interactive soft skills courses.
The activities of the consortium were communicated as appropriate on social media channels (Twitter, Facebook) and international conferences. Of note, PurinesDX ESRs have been actively engaged in outreach from online presence to face-to-face activities.
The therapeutic potential of targeting the P2X7 via antagonists has been validated across a range of different preclinical models of brain disease, confirming our initial hypothesis of P2X7 being a common drug target for brain diseases.
This includes data demonstrating that the P2X7 contributes to drug-refractoriness during epilepsy and that blocking of the P2X7 potentiates the action of currently used anti-seizure drugs (importantly, beneficial effects have also been observed by a P2X7 antagonists, which was developed as part of PurinesDX training programme). We have also data showing that blocking of the P2X7 prevents the toxic effects of tau in tauopathies (e.g. Alzheimer’s disease), and that P2X7 receptor antagonism ameliorates disease progression of ALS. Finally, P2X7 receptor antagonism had also a beneficial effect in models of schizophrenia further demonstrating that targeting of this receptor may constitutes a common treatment strategy for several brain diseases.
A second focus of our research was the identification of disease-specific biomarkers. We have now proof of principal data demonstrating the potential of purinergic signalling based diagnostic approaches including blood purines and the P2X7 itself. This includes data showing blood purines as possible diagnostic for epilepsy and schizophrenia and increases in P2X7 expression as readout of seizure activity.
The PurinesDX programme targets the shortage of researchers with adequate qualifications, skills and experience in Neuroscience. By combining input from researchers and clinicians with expertise in different brain diseases (e.g. epilepsy, schizophrenia with industrial leaders with similar interests in pharmaceuticals, biotechnology, and biosensors), the training programme has provided a new cohort of creative, entrepreneurial and innovative neuroscientists.
This goal has been addressed by implementing innovative individual research projects, which trainined the ESRs in the latest state-of-the-art methods in neuroscience, a rapidly expanding research field. The training programme was further strengthened by a comprehensive inter-sectoral exposure, substantially involving the non-academic sector (industry and clinic). These secondments broadened the researchers’ ability to work on complex problems in existing and future cross-disciplinary research adding to their employability. As projects evolved, training opportunities beyond those forecasted in the proposal were identified and complementary research interactions branched from original projects. It is also noteworthy that this impact extended beyond individual projects and benefited participating principal investigators and organisations (e.g. additional funding due to interactions within PurinesDX, new research lines developed between Partners).
PurinesDX Annual Meeting II