CONTENTS · The American Association of Immunologists (AAI) (Washington, 12–16 May 2016) Dr Madhu Gargesha from MERLIN partner BioInVision presented a paper titled “MSC pre-treatments

MESENCHYMAL STEM CELLS TO REDUCE LIVER INFLAMMATION

WELCOME TO THE AUTUMN 2016 NEWSLETTER FOR THE EU PROJECT MERLIN

CONTENTSMERLIN at a Glance – a reminder of the project’s key aims and objectives............................2Read All About it – details of some of our recent publications ................................................3At the Lectern – some key presentations delivered by the MERLIN team..................................4Progress and Next Steps – where to find progress updates and a look at next steps..........5Meet the Team – the partners behind the project ....................................................................6

The MERLIN team at a project meeting in Padua in 2015

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602363. The material presented and views expressed here are the

responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out.

2|MERLIN newsletter Autumn 2016



It is estimated that 29 million people in the EU have chronic liver disease, and it is the fifth most common cause of death. Primary sclerosing cholangitis (PSC) is a type of liver disease that is rare and poorly understood. Like most liver diseases, PSC involves inflammation that leads to liver damage. In patients with PSC, the bile ducts inside and outside the liver become inflamed and scarred. Scarring of the bile ducts causes a build-up of bile, which then results in tissue damage throughout the liver. The cause of PSC is not known and at present, there is no specific treatment for the disease. The damage caused by PSC means that patients with the condition often need liver transplants.

MERLIN is looking at new ways to treat liver disease with stromal cells from adult bone marrow (MSCs), specifically focusing on PSC as a model disease. Regenerative medicine uses stromal cells to regenerate tissue or organs damaged by disease. However, in order to unlock the full potential of stromal cells, it is necessary to manufacture highly pure cell populations, control how they grow (proliferate) and control what type of cell they become (differentiate). MERLIN will deliver high purity MSCs for therapeutic use, determining the best growth conditions for manufacturing stromal cells and developing new insights into immune response, distribution in the liver, proliferation and differentiation.

In the first phase of the project the MERLIN team have looked at the effectiveness of MSCs against inflammatory liver disease in pre-clinical laboratory models. Results to date have been promising. In the second phase of the project, we are using the outcomes of our pre-clinical work to design and implement a clinical trial, looking at the effect of MSC therapy on inflammation in patients with PSC. The MERLIN clinical trial will set the stage for future work to bring a new, MSC-based therapy for PSC to the clinic.

MERLIN is specifically focused on PSC, but will also generate new knowledge that is more widely applicable to liver disease, to other conditions involving inflammation and to regenerative medicine in general.

MERLIN – at a GlanceA reminder of the project’s key aims and objectives

For more information about the MERLIN project visit our website: http://fp7merlin.eu/

In particular, for project flyers and videos see http://fp7merlin.eu/media-centre/photos-videos-and-presentations/

Video from MERLIN web-site, also available on Youtube https://www.youtube.com/watch?v=l-8HUyhjCr_8

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Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1. (L Zanotti, R Angioni, B Calì, C Soldani, C Ploia, F Moalli, M Gargesha, G D’Amico, S Elliman, G Tedeschi, E Maffioli, A Negri, S Zacchigna, A Sarukhan, J V Stein and A Viola) Leukemia May 2016:5 30(5):1143-54. Doi: 10.1038/leu.2016.33

The therapeutic potential of Mesenchymal Stem Cells (MSCs) is widely acknowledged, but the means by which MSCs affect the immune system is not fully understood. This article deals with the targeting of the endothelium by MSCs during immunity and inflammation.

Extract from abstract: “In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC… Thus, this

study discovers a new and highly efficient general m e c h a n i s m through which MSC tune down immunity and

inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.”

Mesenchymal stem cells: myths and reality. (Adelaida Sarukhana, Lucia Zanottib, Antonella Viola) Swiss Med Wkly. 2015;145:w14229. 23 Dec 2015. Doi: 10.4414/smw.2015.14229

MSCs have become a significant focus for research over recent years, generating numerous studies examining their properties and potential. This article reviews and evaluates published results and looks at the questions that remain unanswered.

Extract from abstract: ”…the number of studies addressing MSC biology and their capacity to treat a broad range of human diseases at the preclinical and clinical level has grown exponentially, with often confusing and conflicting results. The use of poorly defined cell preparations and experimental models, many of them in vitro, has added to such confusion. In this review, we identify what in our opinion remain the main open questions on MSC biology and we attempt to distinguish the facts from the myths concerning endogenous and therapeutic MSC.”

These and other publications related to our work can be found on the MERLIN website at http://fp7merlin.eu/project/the-research-plan/publications-page/

Read all about it!Details of some recent MERLIN publications

Prof Antonella Viola, Universita Degli Studi Di Padova (co-author of the articles above).

MERLIN research results are still being generated, collated and analysed and we envisage many scientific publications in the months ahead, based on our work. However, the team have already released some significant publications. Two recent examples are described below.




EU-MSC2 meeting (Leiden, 07–08 Sept 2015)Several members of the MERLIN team attended and participated in the EU-MSC2 meeting in Leiden. The event brought together researchers from a number of EU-funded projects pursuing MSC research. The projects represented included Stellar, RETHRIM, REACH, VISICORT, ADIPOA-2, REDDSTAR, SCIENCE and NEPHSTROM.

The meeting included interactive panel discussions about key challenges faced when developing MSC therapies (e.g. scientific obstacles, regulatory and ethical issues, technological hurdles and commercialisation

barriers). Opportunities for future collaborations and harmonisation of MSC research in Europe were also discussed.

Following the event, a report of the meeting was published, which is available on the MERLIN website: https://issuu.com/daniellenicholson/docs /eu_msc2_meeting_report/1

ESAL Annual Meeting 2016 (Barcelona, 13-17 April 2016)EASL (The Home of Hepatology) is Europe’s pre-eminent liver association with global reach and influence. At EASL 2016 MERLIN was presented in a bespoke session to highlight EU initiatives. Prof Phil Newsome (University of Birmingham, Coordinator of MERLIN) also presented at the special symposium on systemic inflammation

in advanced chronic liver disease (17 April). Prof Newsome’s presentation was entitled “New concepts for targeting inflammation and immune dysfunction in advanced chronic liver disease”.

The American Association of Immunologists (AAI) (Washington, 12–16 May 2016)Dr Madhu Gargesha from MERLIN partner BioInVision presented a paper titled “MSC pre-treatments lead to better cell survival in mouse models of liver disease: A CryoViz Study” at the American Association of Immunologists (AAI) 2016 Conference in Seattle, Washington.

Dutch Transplantation Society Meeting (Groningen, 9 March 2016) Researchers from MERLIN project partner Erasmus MC recently made a number of presentations at the Dutch Transplantation Society Meeting held on 9 and 10 March 2016 in Groningen. These included a poster presentation about the MERLIN project entitled “Optimizing the immunogenicity and immunomodulatory properties of MSC “, (de Witte S, Franquesa M, Strini T, Korevaar S, Luk F, Elliman S, Newsome P, Gargesha M, Roy D, Merino A, Baan C, Hoogduijn M.).

At the Lectern!Some key presentations recently delivered by the MERLIN team

Since the project began, project partners have been involved in numerous dissemination activities. A selection of key presentations made over the last 12 months are summarised below.

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Progress Updates and Next StepsThe MERLIN team have issued a number of updates on progress since the project began. These annual progress reports are freely available on the project website and include summaries of the scientific work we are undertaking.

Each report sets out a progress update for every work package in the project, dealing with aims, history of work undertaken, recent achievements, current work, challenges and opportunities.

The first annual progress report is available on the website at http://fp7merlin.eu/news/page/3/.

The picture opposite shows the second annual progress report, which can be found at http://fp7merlin.eu/news/.

NEXT STEPSThe MERLIN project began on 1 February 2014. As the project nears completion of its third year, we will be focusing on the follow-ing in the months ahead:

• Finalising our ground work for the MERLIN clinical trial and securing trial authorisations.

• Discussing results and future plans at the project’s plenary meeting in October 2016.

• Analysing data and completing reports on the action, efficacy, proliferation and optimal use of MSCs.

• Preparing interim reports for the EU.• Conducting the MERLIN clinical trial and

analysing results. • Continuing our programme of

dissemination.• Turning our attention to exploitation

of MERLIN’s results and future collaborations between the partners.

Many thanks to the MERLIN Scientific Advisory Board for their continued interest in and engagement with the project. Members (pictured above left to right) Dr. Neil Henderson, University of Edinburgh; Prof Tom Karlsen, Oslo University Hospital; Prof Massimo Pinzani, University College London; Prof Willem Fibbe, Leiden University Medical Center and Prof Ansgar Lohse, University Medical Center Hamburg-Eppendorf (Chair).




PROJECT PARTNERSMERLIN brings academic and clinical experts in stromal cell biology, inflammation and liver disease together with industry leaders in stromal cell manufacturing and advanced imaging, to develop a therapy for patients with PSC. The partners in the project are set out below. For

more details see http://fp7merlin.eu/partners/

University of Birmingham,

United Kingdom

NHS Blood & Transplant,

United Kingdom

Orbsen Therapeutics

Limited, Ireland

Erasmus Medical Centre,

Netherlands

Pintail Ltd,Ireland

BioInVision,United States

Università Degli Studi Di Padova,

Italy

CONTENTS · The American Association of Immunologists (AAI) (Washington, 12–16 May 2016) Dr Madhu Gargesha from MERLIN partner BioInVision presented a paper titled “MSC pre-treatments

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