Epigenetic mechanisms allow cells to adjust gene expression in response to environmental cues. Increased understanding of this area has led to excitement about the potential of applying epigenetic regulation to drug discovery. EPIMAC aims to pursue the potential of epigenetics as a novel and innovative therapeutic modality for immuno-inflammatory diseases, in particular Inflammatory Bowel Disease (IBD). IBD is a severe and disabling chronic inflammation of the gastrointestinal tract affecting millions of people worldwide. Current treatment strategies are not successful because the precise etiology unclear. It is increasingly clear that deregulated epigenetic processes are associated with the aberrant inflammatory response seen in IBD. Recent reports suggest that inhibitors of epigenetic modifications developed by GlaxoSmithKline (GSK), such as histone deacetylase (HDAC) inhibitors, bear potential in treating inflammatory states (Nicodeme et al, Nature 2010; Kruidenier et al, Nature 2012). The EPIMAC consortium has the ambition to educate a group of next-generation scientists that master genetics, epigenetics, target discovery, pharmacology, preclinical validation and regulatory issues, and at the same time have a good understanding of clinical implementations of the drug pipeline of our pharmaceutical partner GSK. GSK is one of the world's leading research-based pharmaceutical and healthcare companies that aims to team up with academic partners in EPIMAC through its dedicated discovery performance unit named EpiNova in conjunction with 2 immuno-pharmacology units. An SME specializing in epigenetic compound targeting to inflammatory cells, Chroma Therapeutics, will contribute technology to EPIMAC. EPIMAC will educate and train these scientists by providing them with a versatile and multidisciplinary doctoral program, allowing them to become excellent scientists skilled to overcome the current challenges in IBD.
Antimicrobial resistance imposes an important health and economic burden with the threat of a future without effective antibiotics requiring major changes to contemporary healthcare provision. Therefore, the discovery and development of novel mechanism of action agents able to treat resistant infections is a key urgent need. Gepotidacin is a first in class, novel triazaacenaphthylene antibacterial that is being developed by GSK. Due to its novel mechanism of action, gepotidacin is active in vitro against most target pathogens carrying resistance determinants to established antibacterials, including fluoroquinolones. Gepotidacin has broad gram-positive activity and selective gram-negative activity and is currently under development as a treatment for infections caused by N. gonorrhoeae (urogenital gonorrhoea) and E. coli (acute uncomplicated urinary tract infections), including isolates resistant to existing classes of antimicrobials. To explore the potential of gepotidacin to treat infections caused by N. gonorrhoeae or E. coli at other body sites, the AB-DiRecT consortium will conduct a tissue distribution study in tonsil and prostate after single oral dose of gepotidacin in healthy (non-infected) subjects undergoing elective tonsillectomy or prostatectomy. Microdialysis will be used to measure gepotidacin levels in tissue following surgery and PBPK, PopPK and PKPD models will be built to understand the tissue penetration of gepotidacin to characterize exposure response and to evaluate different dose regimens. Difference between infected and healthy tissue will be explored in an animal prostatitis infection model where gepotidacin PK in plasma and tissue will be determined using microdialysis. Overall the data generated in AB-DiRecT may support the potential for clinical trials to determine the efficacy of gepotidacin for the treatment for pharyngeal N. gonorrhoeae infections and / or prostatitis caused by E. coli.
The CRYDIS exchange programme will establish and support international and inter-sectoral transfer of knowledge and expertise in pharmaceutical and instrument science between several EU research institutes and industrial companies. It will also enhance understanding of the value of inter-sectoral exchange mechanisms for taking research to market. CRYDIS undertakes innovative, collaborative research on the clinically-important topic of dissolution of drug substance particles in bio-relevant media and the undesired subsequent nucleation and re-precipitation of the drug prior to its absorption. Using innovative advances in UV imaging technology, CRYDIS investigates the utility of novel dissolution assays as key tools to obtain fundamental data on the mechanism and kinetics of undesired nucleation and re-precipitation during or following dissolution, a significant problem for the pharmaceutical industry which struggles to obtain sufficient exposure to poorly soluble drug substances to ensure an effective dose is absorbed by the patient. The key technologies in this proposal offer a step change in capability and functionality, offering the potential to undertake more detailed studies of the dissolution/re-precipitation processes relevant to pharmaceutical materials. Access to this key technology and the further development of its capability offers the potential for breakthroughs in development of process understanding and of robust and widely applicable protocols. Additional value is brought to CRYDIS through close working with synergistic European networks, leveraging a greater knowledge input and impact outreach. Running parallel with the science programme, an innovation management work-package analyses effectiveness of the exchange mechanism in building a shared culture, transferring knowledge and developing understanding of processes that drive a product to market. The outcomes of this will be used to advise and drive potential future exchange activities.