PBCTRAN · Primary Biliary Cirrhosis-Translating genetic discovery into patient benefit

Primary Biliary Cirrhosis-Translating genetic discovery into patient benefit

Overview PBCTrans has set out to understand the molecular immunology of PBC, a rare autoimmune liver disease, from the perspective of translating genetic discoveries into scientific advance. The support over 4 years is a relatively modest amount that has however been very helpful in integrating the work of the awardee, and their team, contributing to larger subsequently funded projects in which they are co-investigators (e.g. UK-PBC funded by the MRC, UK-PSC funded by the NIHR, and the Birmingham NIHR Biomedical Research Unit in Liver). Additionally, it has allowed the awardee to build a holistic programme of research in autoimmune liver disease that since 2012, has flourished and focused on the journey patients with autoimmune liver disease encounter. Thus it has been possible to advance our basic science studies into translating genetic discoveries into biologic meaning, at the same time as building up a group of post-docs and fellows focused on a varied array of relevant studies in autoimmune liver disease, all targeting impact for patients. Impactfully, during the time of the award, the lead applicant (Hirschfield) as a result of a general and broad based clinical science approach to autoimmune liver disease, has been able to work with Industry in pursuit of new therapies, most notably for PBC, and in particular as referenced to Obeticholic acid, the first new licenced therapy for PBC in more than 20 years (Intercept Pharmaceuticals). Additionally from a European perspective the awardee lead the development and publication of the EASL Clinical Practice Guidelines on PBC. Results We have focused efforts from the general support awarded by this career integration award on a) probing the role of IL-12 in the pathophysiology of PBC- we have looked in great detail at the role of IL-12 may have in PBC, given the genetic risk associations described by many. We have focused on studies of both peripheral and hepatic immune cells, and have really been able to identify subtle distinctions that stand out about IL-12 signaling between PBC, a biliary disease associated genetically with IL-12, and PSC, a related but distinct biliary disease that is not genetically associated with IL-12. These data are being finalised for publication, with additional experiments focused on control subjects now being performed. b) establishing how to look at the impact of genetic variation on biologic functioning: we have published in Scientific Reports our proof of concept study that we are able to take new genetic discoveries (in this case the association of CD28 with autoimmune biliary disease), and use healthy individuals to try and understand how genetic change translates into biologic message; c) developing the immunophenotyping expertise to look at transcriptional signaling in immune cell subsets- using the underpinning expertise and experience of working with immune cells from our patients, and in conjunction with the overarching UK-PBC nested cohort study, we are now performing a transcriptomic analysis of immune cells in patients with PBC, stratified by their individual drug response, and evaluated based on the cell type (e.g. Treg, CD4/8). This data, complex in nature and size, is currently being evaluated. d) contributing to national and international consortia involved in autoimmune liver disease research- the fundamental purpose of this award was to ensure career integration for Hirschfield, who over the course of the funding has worked closely with UK colleagues (UK-PBC, UK-PSC, UK-AIH) and internationally (European Reference Network for Rare Liver Disease; International PBC study group; International AIH group; International PSC Study group, the PSC liver forum) to collaborate on scientific, regulatory and clinical projects. e) applying the expertise gained from understanding the science and clinical aspects of autoimmune liver disease to the development and completion of clinical trials for patients. f) using the flexibility of the funding to prime the development of a pan-science and pan-clinical group of investigators at all stages of their career. g) returning value to patients with autoimmune liver disease through educational efforts for patients and clinicians that describe and disseminate science and practice, including presenting work at international meetings (e.g. EASL, AASLD), as well as at local patient support groups. Conclusions PBCTran has been a success. It's goal was career integration for Hirschfield, and this has been highly successful since his move to the UK from Canada in 2012. His group has focused on immune understanding of PBC, and is now well placed to continue independently funded research in the area, in a collaborative and internationally relevant way. Socio-economic impacts The greatest indirect gains have come from the work Hirschfield has contributed to significantly around risk stratification, surrogate markers of disease activity, and the use of a coalition of science and clinical expertise, to be considered a key opinion leader working in partnership with industry for the development of new drugs, and in particular with the development, licencing and reimbursement of Obeticholic acid for patients with PBC.

Data: CORDIS, © European Union