The Research Plan

WP1) Pre-clinical efficacy testing of MSC

Initially, the efficacy of existing purified stem cells (ORB1+ MSC) from Orbsen Therapeutics will be tested in two pre-clinical models of PSC developed at the University of Birmingham, as well as on T cells isolated from patients with PSC. Data from this work will be used to obtain approval for the clinical trial. These pre-clinical models of PSC will also be used to test improved purified stem cells, derived during the MERLIN project.

WP2) Functionality of endogenous MSC

In order to directly compare the behavior of MSCs in our pre-clinical models of PSC with the behavior of MSCs in the clinical progression of PSC in humans, we must be able to identify, isolate and compare MSCs from different species. At present, there is no single marker or combination of markers that allows such identification, isolation and comparison. Preliminary data from within the consortium has identified a possible solution to this problem that will be investigated in this work package.

WP3) Immunogenicity and immunological footprints of MSC in PSC

One of the potential drawbacks of stem cell therapy is an immune reaction against the cells when transplanted into patients. In this work package, the factors responsible for immunoreaction will be identified and manipulated to generate stem cells that are less likely to cause immunoreaction in patients. In addition, the immunological footprint of MSCs used in pre-clinical and clinical applications for PSC will be characterized in order to generate novel in vivo immunological potency assays.

WP4) Mechanism of Action of MSC in models of liver damage in vivo

MSCs are known to have anti-inflammatory effects in liver disease but the location and mechanism of these effects are not clear. This work package will investigate the environmental requirements and the specific molecule(s) responsible for MSC immunomodulation in vivo. It will also determine how MSCs suppress inflammation through actions on liver vasculature.

WP5) Genetic, biological and pharmacological enhancement of ORB1+ MSC

In order for MSCs to be adopted as a treatment for PSC, it must be possible to reliably isolate, grow, preserve and transport the cells. This work package will develop procedures for handling MSCs during the project that meet Good Laboratory Practice (GLP) requirements. The effect of growing and preserving MSCs on the efficacy of the cells will be assessed in a pre-clinical model of liver injury. Drugs that may be used to improve the efficacy of MSCs will also be screened.

WP6) Advanced tools for bio-distribution of MSC

In order to better understand how MSCs function in the treatment of liver disease, it is necessary to determine where MSCs are distributed after infusion. It is also necessary to determine how many cells survive the transplantation and how they proliferate in the liver with time. This will be achieved using CryoVizTM technology from BioInvision Inc., which will be adapted to carry out high throughout ‘array-imaging’ of liver samples in 3D.

WP7) Investigational Medicinal Product Dossier & Manufacture of Clinical Grade ORB1+/- MSC

An investigation medicinal product dossier (IMPD) will be developed, using data from GMP-like process development, quality control assays and manufacturing validation studies. During this work package, there will be a GMP transfer of ORB1 protocols from Orbsen Therapeutics to NHS Blood and Transplant and a full scale manufacturing validation study will be carried out. GMP-grade MSCs will be manufactured for use in the MERLIN Phase 2a clinical trial.

WP8) Phase 2a Clinical Trial of ORB1+/-

There is currently no medical therapy for patients with PSC. MERLIN will undertake a Phase 2a clinical study of MSC therapy developed during the project to determine the efficacy and safety of the therapy, as well as the indication for use. Results from this study will inform future Phase 2 and 3 studies. The trial will be carried out by the University of Birmingham.

WP9) Data and samples management

Effective data and samples management are essential in a large-scale, international research project. In MERLIN, samples and pre-clinical data will be generated at a number of sites. In order to facilitate efficient sharing of data across the project, Pintail Limited will develop a customized, secure shared data repository, based on their StudyVault platform. Samples will be managed centrally by NHS Blood and Transplant, who will identify, schedule, monitor and verify the movement of all samples within the consortium.