Programmed cell death is essential for homeostasis, and its deregulation contributes to human disease. Inflammasome-induced pyroptosis of infected macrophages contributes to host defense against infections, but the concomitant release of inflammatory danger signals and leaderless cytokines is detrimental in chronic inflammatory diseases. The central hypothesis of the PyroPop ERC Consolidator project is that inflammasomes are cytosolic platforms that couple pathogen sensing to multiple programmed cell death modes. This is based on our preliminary data showing that inflammasomes can be triggered to switch from inflammatory pyroptosis to programmed necrosis and non-inflammatory apoptosis. This suggests that the (patho)physiological outcomes of inflammasome activation may be modulated for therapeutic purposes. However, the molecular machinery and effector mechanisms of pyroptosis, inflammasome-induced apoptosis and programmed necrosis are virtually unknown. My objectives are (i) to explore the cleavage events and subcellular dynamics of pyroptosis by proteomics and high-resolution time-lapse microscopy; (ii) to clarify the molecular mechanisms of pyroptosis and inflammasome-controlled cell death switching; and (iii) to address how inflammasome-associated cell death modes impact on anti-bacterial host defense and chronic inflammatory pathology in vivo through the identification of pyroptosis-selective biomarkers and clinical analysis of pyroptosis-deficient mouse models. The central hypothesis in this regard is that inflammasome-mediated secretion of leaderless cytokines (such as IL-1β and IL-18) and danger signals may be mechanistically coupled to pyroptosis, but not apoptosis induction. By clarifying the mechanisms of inflammasome-controlled programmed cell death, this project may set the path for the development of an entirely novel class of inflammation-modulating therapies that are based on converting inflammatory pyroptosis into non-inflammatory apoptosis.

Drug discovery is a time consuming, expensive and risky process. Each drug to market must undergo safety/ toxicity testing in animals which yields thousands of tissue sections that currently must be assessed manually by a trained veterinary pathology. However, there is a looming crisis due to the lack pathologists. The PATH-TOX consortium is led by Irish SME, Deciphex Ltd, and includes key partners such as Janssen Pharmaceuticals in Belgium and Pathology Data Systems Ltd a Swiss based SME. They are creating PATHOLYTIX-TOX a computer aided diagnostic system to streamline the pathology review process. Using state-of-the-art artificial intelligence (AI) image analysis tools it will automatically identify the normal and abnormal tissues upfront, allowing the pathologist to focus mainly on the abnormal cases, hence accelerate workflow. To date, we have built a working prototype of the image analysis engine, which can identify abnormal tissue in liver. In this project we will optimise the engine further to improve performance and expand its use into other tissues. We will also develop other features such as the user interface, data management and cloud framework. Once developed, we will perform a comprehensive validation and benchmarking study to compare to manual pathology assessment. There is a large, growing, global target market for PATHOLYTIX-TOX. Pharma and CROs worldwide routinely perform thousands of animal toxicology tests each year, who are potential customers. With regards to competitors, there is no direct competition. Competitors offer individual components of the pathological workflow, not fit-for-purpose solutions for the toxicology pathology market. Overall, PATHOLYTIX would have a big impact on drug development, by reducing the time required for pathology review and associated costs. This should have a knock on effect for the global and EU markets, reducing time and cost for new drugs to get to market.

LongActNow will design a novel platform technology for the development of long acting (LA) suspensions of complex active pharmaceutical ingredients (API), involving innovative manipulation of API crystal formation and growth and solvent removal. LA formulations have become a game-changer in terms of bringing existing and new API in more cost-efficient and comfortable ways to patients, often directly impacting commercial viability of new products. However, existing technology platforms are only applicable to a limited part of the pharma portfolio and do not allow to fully unlock all benefits linked to LA. LongActNow is a unique European Industrial Doctorate (EID) initiative that aims to meet the current and future demand for highly skilled scientists and engineers in pharmaceutical development and manufacturing of LA formulations. The initiative is leveraged by fusing the capabilities of four significant international academic and industrial centres (University of Limerick (UL), Trinity College Dublin (TCD), Technische Universität Dortmund (TUD) and Janssen Pharmaceutica (Janssen)) with specific expertise in crystallisation, solution behaviour, modelling, solvent switching, pharmacokinetics and formulation. LongActNow will advance European research in the field of crystallisation technologies, more specifically the design, development and optimization of prediction and production technologies to produce medicines with well controlled physical and pharmacological properties. The project will produce five Early Stage Researchers (ESRs) trained in crystallisation and formulation to a PhD level with a unique capability to optimise the stability and duration of activity of injectable suspensions for complex APIs and will nourish the creativity, entrepreneurship, management and business skills of ESRs in the domain of drug development and manufacturing, to stimulate an innovation-oriented mindset in future pharmaceutical researchers.

Communication strategy and tools for optimizing the impact of Ebola vaccination deployment. The EBODAC consortium consists of 4 partners: Janssen (EFPIA), London School of Hygiene and Tropical Medicine (LSHTM), World Vision of Ireland and Grameen Foundation . These partners have experience and expertise in: • (Ebola) vaccine development and vaccine acceptance; m-health deployments for disease management in resource limited settings (Janssen) • Vaccine acceptance; risk management in health programs (LSHTM) • Mobile health deployments for emergency assistance; communication and training delivery in emergency settings (World Vision) • Mobile health software development and deployment in resource limited settings (Grameen) As such, the EBODAC consortium is well placed to tackle the challenges associated with Ebola vaccine deployment, including: • Stigma related to Ebola infections • Lack of understanding and distrust versus vaccines in general in the local endemic communities • Two step prime/booster regimen for Ebola vaccine: risk for a ‘no show’ for the booster shot, risk for presenting for the booster shot too early or too late; risk for a different person presenting for the booster shot vs. the prime shot • People may be difficult to reach for the vaccine recall; People may live at a large distance from the health center where the vaccine is delivered • Risk for data on vaccine coverage to be fragmented, not existing or incorrect The EBODAC consortium is committed to deliver: • A communication strategy that will optimize vaccine acceptance, supported by local anthropology research data • A platform, based on mobile phone technology, for Ebola vaccine recalls, information/education on Ebola and vaccines in general; and tracking of vaccination coverage • An identification tool to allow to match the identity of individuals in the prime and boost vaccine regimens • A training program in the local setting, and a helpdesk function, to support the m-health platform

With over 25% of the global disease burden, only 3% of global clinical trials occur in Africa. This disproportion is driven by inadequacies in clinical research capacity, regulatory process ambiguity, deficient regional patient and disease area data, and lack of visibility of existing clinical research capabilities in Africa. To address this disproportion, this proposal seeks to establish the Clinical Trials Community Africa Network (CTCAN), a collaborative framework of key clinical research stakeholders in the African region, pharma partners, and other relevant international stakeholders, with the overarching goal of bringing more clinical trials to the region in a sustainable and coordinated manner. This collaboration will map and draw on the experience and expertise of already existing networks and initiatives. It will create a network of subnetworks that will foster coordination in clinical research, by ensuring and encouraging alignment in disease area prioritization, raising awareness and visibility of existing capacity from sites and labs across Africa, operationalising the regulatory processes across the region, and strengthen less experienced sites and labs through a clinical trial preparedness framework, while encouraging inter- and cross-continental knowledge and expertise sharing. CTCAN will use and expand the Clinical Trials Community (CTC) platform, an electronic platform consolidating data on researchers, regulations, sites, and epidemiology across the continent. The result will be an ever-present and ready-to-go pool of clinical research sites and labs with the agility to rapidly address new and emerging global health threats, epidemics, and pandemics, thereby efficiently contributing towards clinical research in pandemic preparedness. CTCAN will lay the foundation for a sustainable network of clinical trial sites and laboratories in sub-Saharan Africa by leveraging and initiating collaboration between existing sub-networks, funders, and pharma.