The Pluripotent Stem Cells and Engineered Cell (PSEC) Hub

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The ability to repair the injured or diseased human body with human pluripotent stem cell (hPSC) derived products is emerging as a realistic therapeutic option. However this brings with it a number of major challenges; 1) Can this be done safely? 2) Can this be done usefully and competitively? i.e. it the treatment as good or better than what is available; and 3) Can we do this at the scale needed to treat all patients that might require this type of therapy? In this new hub we will work on these issues around two particular therapeutic agents. The first involves making dopamine nerve cells to replace those lost in the brain of patients with Parkinson's disease (PD). The second involves making a specific component of blood that is vital for clotting- namely platelets generated from hPSC-derived megakaryocytes. These two cell products and the diseases linked to their use are not seen as the primary output of this grant, but rather will serve to contextualise our work, which is primarily designed to build a platform by which any hPSC-derived therapy can be brought to the clinic. We have three major aims: The first relates to acquired genetic changes seen in cells grown in the laboratory and what this means for the safety of our hPSCs/cell products. Every cell has DNA, which contains all our genes, and between cells, there will be natural variations along with random errors and mistakes. Many of these changes are of no consequence, while others may be potentially harmful. The question we need to answer is can we reliably detect the bad genetic variants in the hPSCs and the cells we produce from them, while also recognising those genetic changes that are unimportant and can be safely ignored. This is obviously not an easy question to answer, but what we will do, is look at the changes in the genes in a number of different hPSCs/products and then compare what we find with databases that contain information on the links such genetic changes have to known human diseases and cancers. This will allow us to develop guidelines, which will then hopefully be adopted by the relevant regulatory agencies and applied to any hPSC-derived therapy going to clinic. Our second aim is to address the major issues related to how we can manufacture our hPSC-derived products in the numbers and quality required for clinical use in large numbers of patients. Currently, many of the protocols we have developed in the lab, work well, but the reagents we use are not of the grade needed for use in patients- so called GMP grade. Thus we will seek to develop the necessary clinically compatible protocols and then work out how we can scale up and scale out the manufacturing of the cells we are interested in developing so that ultimately all relevant patients could benefit from these types of treatment. For some diseases, this will be quite straight forward, as we only need relatively few cells to treat patients- e.g. 500,000 to a million cells for a single patient with PD. In other conditions, we will need millions and billions of cells, such as platelets, and this creates huge challenges for manufacturing. We will therefore work on ways to do this, such that we can reliably and reproducibly do this at the level needed for clinical use. Our final major aim is to develop new techniques to make our cell therapies work better when transplanted. This will involve two main approaches; (i) Techniques to allow us to make the cells we want more efficiently, i.e. so we can manufacture large numbers of cells from our hPSCs as will be needed to treat patients and; (ii) Silencing critical molecules/proteins in the cells that trigger immune rejection, i.e. so that when the cells are grafted into patients their immune system will react to them less vigorously. This in turn will mean that we can use less aggressive immunosuppressive regimes to stop the grafts being rejected and by so doing reduce any side effects from these drugs.