The Pluripotent Stem Cells and Engineered Cell (PSEC) Hub

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.

We will deliver a platform of technologies and expertise that will enable new human pluripotent stem cell (hPSC) based therapies to more readily enter the clinic. This will be done around 2 major therapeutic areas - hPSC derived dopaminergic neurons and megakaryocytes. These exemplars will contextualise the overarching aim of the hub which is to further understand and develop the next generation of genetic and reprogramming tools needed to allow ANY hPSC-based product to progress to clinic. This will be done through 3 major research programmes: THEME 1 - CELL CHARACTERISATION AND STABILITY: We will assess the phenotypic consequences of specific genetic variants using our clinical exemplars, while also developing sensitive high-throughput detection methods for genetically variant cells. We will the use this information to optimise culture conditions to suppress the appearance of concerning genetic variant, while also producing lists of non-consequential genetic variants that we detect which we will then feed into international guidelines for adoption by relevant regulatory agencies. THEME 2 - IDENTIFYING AND MODELLING KEY DETERMINANTS OF MANUFACTURING OUTCOMES FOR HPSC PRODUCTS AND PROVIDING A REGULATORY ROADMAP: We will address issues to do with manufacturing cells in the quantity and the quality required, for clinical adoption using dynamic process models as well as novel protocols and reagents. This will include a pathway for regulatory integration, to facilitate clinical application and first in human studies. THEME 3 - UNDERSTANDING ROUTES TO DIFFERENTIATION: We will develop a new generation of genetically modified hPSCs with improved differentiation capabilities including purity, cell yield and reduced dependence on expensive media and/or complex cytokine cocktails as well as reducing their immunogenicity such that they can more easily be employed in the clinic without the need for major immunosuppressive anti-rejection therapies and their associated risks.

The impact of our work has already been discussed in part in the section on "Academic Beneficiaries". In essence the work that will be done in this hub has the potential to enhance and transform the UK landscape around hPSC therapies and regenerative medicine in the broadest possible sense.

The hub will generate outputs that will define the significant acquired genetic changes seen in hPSCs and their products and what this means. This will then be used by regulatory agencies to develop guidelines that are likely to be adopted worldwide. This will impact on all hPSC based therapies being developed for clinical use anywhere in the world where there exists an overseeing national agency - e,g, MHRA; EMA, FDA and so on. Furthermore we will also start exploring not just the acquired genetic variation that comes with growing and differentiating these cells, but how this can be better controlled, especially during any manufacturing process and storage of the derived cell products. Finally we will start to explore this at the level of the epigenome which is likely to represent the next level of regulatory scrutiny as more of these cells move into the clinical space.

The second major impact will be in the undertaking of new clinical trials with hPSC derived products and how this can best be done using the emerging genetic engineering and differentiation protocols that have been developed in recent years. The ability to do this in the research lab is well established, but how this can then be done using clinical grade cells, that need to be made reproducibly in a GMP facility, is still unknown. We will address this issue which will impact on any group wishing to adopt similar strategies with their cell products. This work in turn will impact on the future treatment of patients with a whole variety of diseases as well how this can best be delivered in the context of the NHS, and the wider medical market, at an affordable price.

The third major impact will be in terms of the UK regenerative medicine landscape and investment both from funding agencies supporting hPSC based product development by academics as well as biotech companies and big pharma, both nationally and internationally. The investment that has already been made by the UK in this area is impressive (National Stem Cell Bank; Cell and Gene Therapy Catapult etc), but the work we propose will make the UK the optimal location for developing and trialling hPSC derived products. Indeed to date, we have already worked with other groups outside the UK who do not have the national framework and initiatives that we do around hPSC therapies, and thus the investment in the regenerative medicine market is likely to become a major growth area in the UK economy going forward driven in part by the work we are doing through this hub. This will become an increasingly important asset in the UK post Brexit.

Finally our work will impact on many other groups. This will include the greater scientific community and especially those scientists working with hPSCs in the future and in particular how they can optimally culture the cells and the way in which they can be best manipulated genetically for therapeutic use. The patients for whom these therapies are being developed will clearly directly benefit from this work which could have a major impact on how these diseases will routinely be treated in the future. This will lead to a wider discussion at the societal level as to how we see such therapies from an ethical and therapeutic perspective, as well as what we are prepared to pay for them and how all these issues can best be discussed and presented.

In summary the programme of work we propose has the ability to significantly change and impact on the UK such that it will be seen as a global centre for hPSC based regenerative medicine, leading the world in how this can best be done in terms of minimising risk while optimising their speed of development for clinical adoption.