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MERLIN Report Summary

Project ID: 602363
Funded under: FP7-HEALTH
Country: United Kingdom

Periodic Report Summary 2 - MERLIN (MEsenchymal stem cells to Reduce Liver INflammation)

Project Context and Objectives:
It is estimated that 29 million people in the EU have chronic liver disease, and it is the fifth most common cause of death. Most liver diseases involve inflammation that leads to liver damage. MERLIN is focused on developing a stem/stromal cell therapy for primary sclerosing cholangitis (PSC), a liver disease for which there is currently no treatment. Like most liver diseases, PSC involves inflammation that leads to liver damage. In the absence of effective treatment, damage from the disease means that patients often need liver transplants.

Researchers in MERLIN have been looking at the effectiveness of mesenchymal stromal cells (MSC) against inflammatory liver disease in pre-clinical models, in order to help develop a novel cell therapy for PSC. A clinical trial has been designed based on the outcomes of our pre-clinical studies. The trial will look at the safety of the MSC therapy, examine the effect of therapy on inflammation in patients with PSC and set the stage for future work to bring a new, MSC-based therapy for PSC to the clinic. In addition, through the pre-clinical studies and clinical trial, MERLIN will generate new knowledge that is more widely applicable to MSC therapy in general, informing the development of therapies for other forms of liver disease and other inflammatory conditions.

MERLIN will also work to address a number of general challenges currently faced in the development of cell therapies. Current MSC cell manufacturing approaches have a number of shortcomings that limit their translation to clinical therapies. To date, commercially manufactured MSC have been of a low purity. Progress to larger-scale clinical trials and to mainstream clinical use will require MSC of greater purity than currently available. To address this shortcoming, MERLIN is using novel cell isolation platforms based on proprietary technology and has established a GMP-compliant manufacturing process that yields MSC suitable for use in humans.

The manufacturing process for MSC therapies involves growing cells isolated from biological material, such as bone marrow or umbilical cords, under controlled conditions. Up to now, the optimal conditions for growing such cells was not known. As part of the project, MERLIN researchers are looking at ways to improve the functional lifetime of MSC, reduce the potential immune response to MSC given as therapy and improve how cells are targeted to specific organs. Once the best conditions have been identified, MERLIN researchers will test the safety and effectiveness of these ‘optimised’ MSC in pre-clinical models.

Little is known about the distribution of MSCs in the body (bio-distribution) or how they work once they are administered to patients (mechanism of action). MERLIN is undertaking comprehensive mechanistic and whole-animal bio-distribution imaging studies to further our understanding of how MSCs affect inflammatory diseases.

In summary then, MERLIN is looking at new ways to treat liver disease with MSC, specifically focusing on PSC as a model disease. In order to unlock the full potential of MSC, we have designed a manufacturing process that delivers MSC of high purity, suitable for therapeutic use. We are also developing new insights into MSC and immune response, biodistribution and differentiation.

Project Results:
In the first phase of the project the MERLIN team have looked at the effectiveness of MSC against inflammatory liver disease in pre-clinical laboratory models. We have also explored mechanisms of action of MSC and optimum conditions for MSC production. In the second phase of the project, we have used the outcomes of our pre-clinical work to design a clinical trial, looking at the effect of MSC therapy on inflammation in patients with PSC. Some of the most significant results from our work to date are set out below.

We have shown that MSC reduce markers of liver damage and inflammation in mouse models of inflammatory liver disease, as well as the number of inflammatory cells present in damaged areas. Efficacy was seen at the lower dose of cells used. Sorted CD362+ UC-MSC have significant potential to reduce biliary duct proliferation compared to unsorted UC-MSC. Freshly thawed MSC are as effective as MSC used fresh from culture or freshly thawed and washed (when used in murine models of liver damage). Our data also suggests that route of infusion of umbilical cord (UC) MSC has no impact on therapeutic efficacy (MSC infused subcutaneously were as effective as MSC infused intravenously).

Mechanism of Action:
Using our innovative 3D imaging system, tailored for the project, we discovered that MSC injected under the skin do not migrate to other locations. Even though the MSC remain at the site of injection, they still reduce inflammation in other areas of the body. This indicates that the effects of MSC on inflammation are possibly due to cytokines released by the cells (soluble mediators).

We have studied the specific targets of MSC anti-inflammatory action. A comprehensive analysis of MSC secretome has provided a plethora of pharmacologically targetable molecules for the treatment of inflammation. The proteomic analysis of MSC secretome has identified TIMP-1 as a potential effector molecule responsible for the anti-angiogenic properties of MSC.

Our results also indicate that CD362 has a role to play in the mechanism of MSC.

Immune Response and Optimisation:
Recognition of MSC by patients’ immune systems is a potential complication of MSC therapies. We have found that UC MSC are immuno-privileged, meaning that they are less susceptible to immune recognition than MSC harvested from bone marrow. Our results also show that the immunogenic and immunomodulatory properties of MSC are influenced by culture conditions. We have identified conditions/treatments that enhance the properties of MSC, which offers the possibility to generate MSC for therapeutic use with better properties than MSC currently used for clinical trials.

As noted above, MSC injected under the skin do not migrate to other locations. There is evidence from imaging analysis that dispersal of sorted MSC may be greater from injection site than wild-type MSC. Notwithstanding the remote action of MSC, where there is systemic delivery of MSC we have found a greater number of cells in the liver in CCL4 injury and MDR2-KO injury mice, as compared to uninjured (control) mice. This suggests that injured livers produce factors that attract/retain/promote survival of MSC. All differently treated MSC were largely located in the lungs after administration, with an accumulation of dead MSC in the liver 24h after infusion.

MSC Manufacture and Clinical Trial:
Our work to date has allowed us to develop a process for MSC production from UC tissue that is consistent and MHRA compliant. Our approach represents a significant advance beyond traditional, commercially manufactured MSC, which are of low purity. The MSC we produce will be used for the MERLIN clinical trial.

A significant highlight of our work in period 2 has been the submission of the MERLIN clinical trial application to the MHRA and related ethics submissions, paving the way for the phase IIa MERLIN clinical trial to commence in 2017. UK REC (ethics) and UK MHRA approval for the trial have now been received.

Potential Impact:
MERLIN is a truly multi-disciplinary project, including the generation of new knowledge about the bio-distribution and mechanism of action of MSC, the development of advanced technologies (3D imaging and processes for GMP-compliant manufacturing), and the delivery of an early phase clinical trial. As such, the project will have impact on future research, manufacturing of MSC for clinical use and cell therapies for patients with PSC and other inflammatory diseases.

Patients with PSC, who currently have no treatment options, will benefit from the project. Through delivery of the Phase 2a trial, MERLIN will provide important safety and preliminary efficacy data for a novel MSC therapy. By focusing on understanding how the therapy works to fight inflammation, we are also learning important lessons that can be used in the future to develop MSC therapies for other types of liver disease and for inflammatory conditions in general. Patients will be informed of our results through our strong links to patient groups, in particular the PSC Support group in the UK. In addition to potential benefits for individual patients and their families, improving treatments for liver disease will also benefit healthcare systems through the reduction of costly liver transplant procedures and care costs associated with chronic liver disease. From a health economics perspective, MSC therapies for immune and inflammatory diseases offer potential for significant savings in the longer term.

Researchers in liver disease, immunology and regenerative medicine will benefit from the new knowledge that we generate during the project. For researchers in liver disease and in the broader field of immunology and inflammatory conditions, MERLIN will provide extensive new data on the use of MSC to modulate immune response and to treat inflammation. The project will also have a significant impact in the field of MSC research. We are disseminating our findings widely through publications, presentations at scientific conferences and interactions with other projects. Importantly, MERLIN is part of a larger group of sister projects with many shared partners, providing an extensive network of researchers with whom we can share ideas and results. An additional benefit derived from the project will be the advancement of 3D imaging technology, which offers researchers new, better ways to carry out bio-distribution studies.

The European stem cell therapy industry will also benefit from the project. We have established GMP compliant processes and quality control tests to manufacture high purity MSC that will meet the current and emerging regulations for MSC therapies. In addition, our research is exploring the production of even better MSC through optimisation of the manufacturing process. The project will deliver important data to enable the tailored production and use of MSC which have the precise characteristics (in immune tolerance, longevity, bio-distribution) required for particular applications. In order to ensure that our innovations are of use to the industry, we are focused on ensuring that our advances meet the requirements of regulators.

The MERLIN consortium is committed to building on the project in future collaborations, generating long-term research value and delivering societal and economic benefits through the development of advanced MSC therapies.

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