Pluripotent Stem Cell Platform -Capital Investment

Advances in human pluripotent stem cells (PSC) biology provide unprecedented opportunities to generate safe donor cells for all human tissues and organs in virtually unlimited numbers. Harnessing these advances will enable an array of novel cell-mediated therapies. Realising these ambitions requires a translational structure that melds fundamental discoveries into a pipeline for medical products and applications. The Pluripotent Stem Cell Platform (PSCP) is such a translational alliance, bringing together the Sheffield Centre for Stem Cell Biology, the WT/MRC Stem Cell Institute, Cambridge University Health Partners, the Loughborough led EPSRC Centre for Innovative Manufacturing in Regenerative Medicine, the Wellcome Trust Sanger Institute, the Babraham Institute and NIBSC, to exploit advances in PSC biology for the development of regenerative medicine.

PSCP will implement a translational research programme to reach the following goals: i) protocols for transgene-free, EUCTD-compliant, production, expansion and safety qualification of PSC; ii) methods to minimise occurrence of functionally significant genetic or epigenetic variants during PSC manufacturing; iii) standardised PSC differentiation protocols for deriving, manufacturing and banking therapeutically relevant lineage-specific intermediate stem cells; iv) qualified processes for manufacturing regulatory compliant PSC products suitable for clinical use. To reach these goals the PSCP will address three themes. Theme 1, "Cell characterization and stability", will provide a platform for derivation and validation of EUCTD compliant iPSC and protocols for GMP scale up of PSC, as well as identification of quality acceptance criteria to enable standardisation and transition to automated platforms. It will also provide tools for monitoring genetic and epigenetic changes in PSC and culture refinements that minimize deleterious variants, and an assessment of potential risks posed by these variants for regenerative medicine. Theme 2, "Understanding routes to differentiation", will provide protocols for expansion of PSC-derived neural progenitors with stable potential for differentiation into dopaminergic and otic neurons and also for the generation and expansion of endodermal progenitors. It will address the integration of biology with process engineering and manufacture, including assessment of manufacturing and supply requirements and identification of preferred production system and technology configurations and associated risk assessments and mitigation strategies. Theme 3, "Quality control, safety and reproducibility", will optimise the detection of adventitious agents that may compromise safety, and provide reference standards. It will determine the barriers to operational GMP for our chosen clinical exemplars at acceptable cost of goods within a viable business model and address the key issues of reproducibility and comparability by establishing a scaleable manufacturing process and measurement system capable of allowing demonstration of comparability at three sites.
PSCP will actively engage in networking with other groups, notably with the Catapult and other industry partners, and with Prof Yamanaka and CiRA (Kyoto, Japan), which will enable a rapid start in iPSC production and provide the highest level of international bench-marking for the Hub. PSCP will organise three workshops addressing manufacturing, safety and standardisation, and clinical delivery technologies. The workshops will aim to develop a consensus on 'principles of best practice' for manufacturing, risk assessment and safety testing pertaining to the candidate cell therapies. PSCP will adopt an open innovation model for pre-competitive research with bioindustry, with the intent of engaging with an industry consortium to design and execute a set of demonstration projects focused on generic issues in stem cell manufacturing, notably analytical measures of cell quality, genetic integrity and potency.

The Pluripotent Stem Cell Platform (PSCP) will build upon and integrate emerging PSC technologies with advanced cell manufacturing technology to establish optimised processes for consistent, scalable, production of PSC and their derivatives that meet the requirements of clinicians, regulatory authorities and industry for cell therapy applications. In this way PSCP will establish a leading position in the field of stem cell product development for clinical trials and its potential for industrialisation. PSCP will concentrate in-house activities on PSC and derivative tissue stem cell intermediates. However, the field in general will also benefit from tackling key knowledge gaps including: (i) establishment of standardised systems for generation of robust genetically stable human PSC populations suitable for therapeutic translation, (ii) development of genetic modification tools that bypass the risk of insertional mutagenesis and are subject to science based risk assessment, (iii) development of effective, reliable and reproducible differentiation protocols yielding functional, clinically compliant tissue-specific donor cells, (iv) quality control systems suitable for consistent manufacturing of stem cells and differentiated progeny suitable for use in human applications. The PSCP programme will address these issues through the following workpackages: i) Methods for iPSC production for clinical applications; ii) Development of a GMP-ready PSC expansion platform; iii) Assessment of the genomic and epigenomic integrity; iv) Development of protocols for production of neural progenitors; v) Development of protocols for production of endoderm lineages; vi) Product and process evaluation - integration of biology with process engineering and manufacture; vii) Safety qualification of PSC for clinical application.; viii) Process development for viable and cost-effective GMP of exemplars,notably dopaminergic and otic neurons; ix) Reproducibility and comparability.

The PSCP will ultimately benefit patients by providing underpinning knowledge and expertise to support companies engaged in the development and manufacture of regenerative medicine applications of human pluripotent stem cells (hPSC) (e.g. Neusentis, GSK, ACT, Viacyte), as well as to companies providing tools to facilitate these developments (e.g. LifeTechnologies, TAP Biosystems, Stem Cell Technology), and the UK Cell Therapy Catapult. It will also provide knowledge to assist the healthcare regulatory agencies (e.g. MHRA) as they develop formal regulation and guidelines for authorisation and safe application of regenerative medicine, as well as benefit companies developing in vitro assay systems for drug discovery, disease modeling and toxicology.
PSCP translational advances in PSC technology, tissue progenitor cell expansion and manufacturing will facilitate progress towards realising PSC-based cell therapies. Focusing on overcoming the limited availability of donated tissues and organs, PSCP will provide a pathway to deliver therapies that provide solutions to currently challenging healthcare problems and unmet needs for large numbers of patients. PSCP will fundamentally advance and improve processes required to turn stem cells into products for therapy and will actively embrace the need for standardisation and the demands of regulation, so that cost effectiveness is optimised by providing regulation-proofed and less error-prone manufacturing and analytical processes. In particular, PSCP will aim to achieve the quantities of cells needed for multi-patient therapy using cost effective manufacturing strategies. Further, the PSCP attention to quality standards, biological standardisation and issues such as adventitious agent risk, rapid QC testing and comparability, will enable the UK to consolidate and expand its international position in cell therapy. The PSCP will provide knowledge to assist the healthcare regulatory agencies as they develop formal regulation and guidelines for authorisation and safe application of regenerative medicine.
By integrating the high quality but dispersed capabilities of the partners into a cohesive alliance the resulting consolidated and competitive regenerative medicine hub will provide an enhanced environment for retention and recruitment of leading researchers. This close-knit community of partners will create a hub with cross-disciplinary collaborations to address the technical and scientific challenges associated with translating promising scientific discoveries in the regenerative medicine area into regenerative therapies. This will ensure that the UK can remain at the forefront of the global regenerative medicine field. The PSCP will link basic and clinical research groups which will create interactions based on research excellence and address the current challenges of clinical grade manufacturing of pluripotent stem cells and their progeny in an innovative and effective manner. By co-ordinating our activities with the other RMP hubs we aim to provide cells, protocols, tools and resources which can be used more generally by other UK research groups, academia and industry.
Key findings of PSCP research will be published in Open Access high quality research journals. PSCP partners will present at major scientific meetings including the International Society for Stem Cell Research and International Society for Cell Therapy. Genomic and other high throughput datasets will be deposited in public databases. Our communications strategy, including development of a PSCP website, will ensure engagement, communication and dissemination of the results with the research community and, where appropriate, with the lay public, policy-makers, regulators and administrators.