Cell and gene therapies are promising treatments for several unmet medical needs. Most of these therapies rely on viral vectors as the delivery tool for cell modification. HEK-293 cell line is the most used platform for the manufacturing of cell and gene therapy viral vectors that have achieved successful clinical data and regulatory approval for commercialization. However, the production capacity of this platform is still inefficient to meet the current and growing future demand for viral vectors which leads to the need for large volume bioreactors and high manufacturing costs. Several attempts described in literature to genetically modify HEK-293 cells to improve viral vector titers have resulted in modest improvements in productivity. In this project, we aim to increase viral vector productivity at least 50-100 folds higher by the genetic modification of the 293 cell line targeting genes with crucial role in viral vector production and quality. For that, functional genomics analysis will be used for the gene identification instead of a comparison gene by gene approach as previous attempts. By using functional genomic analysis, the focus will not only be on the genomic but also a combination of epigenomics, transcriptomics, proteomics and metabolomics. As a result, a HEK-293 cell line adapted to serum-free media and in suspension growth will be genetically modified using CRISPR gene editing, At the same time, within the frame of this project, a single plasmid technology will be developed to achieve process cost-reduction and simplicity. In order to support the process development and the screening of the higher producer clones, a fully automated instrument will be developed for virus detection. Furthermore, the manufacturing process of the high-producer cell line will be established and validated at large scale bioreactors. The successful development of this project will deliver a highly productive viral vector manufacturing platform able to provide high yields and high-quality products in a cost-effective manner which will ultimately be at the service of the biotech community to accelerate the clinical translation and affordability of advanced therapies.

"Non-invasive prenatal testing (NIPT), the analysis of cell-free fetal DNA (cffDNA) from the maternal blood, has proven to be more reliable in detecting common fetal trisomies than conventional serum screening and ultrasound. Due to the higher accuracy of NIPT, fewer pregnant woman will have to undergo diagnostic invasive testing which carries a risk of miscarriage. Analysis of cffDNA for detection of trisomies is technically challenging because the maternal plasma contains low amounts of highly fragmented cffDNA in a majority maternal DNA background. Companies and laboratories developing or performing NIPT are in great need of reference standards that accurately mimic clinical samples to validate their different testing platforms and methodologies to ensure accurate test performance on this challenging sample type. At present there is no appropriate reference material for NIPT on the market. This project aims to develop reference standards for NIPT to enable the widespread implementation of accurate, non-invasive screening for chromosomal abnormalities in early pregnancy. Reliable NIPT results will reduce the number of pregnant women undergoing invasive testing to those with a positive test result only. This will improve patient outcomes and reduce the healthcare and socio-economic costs of aneuploid pregnancies and live births."

Genetic engineering (GE) is an established tool for R&D and promises to become a globally used approach to correct and treat important diseases, such as cancer and genetic disease, and also able to tackle and solve important environmental issues. Current approaches are dependent upon manual labour and extensive screening, and are highly inefficient and time-consuming. CRISPR/Cas9 technology, a powerful new form of GE, has now triggered a step-change in the range, precision and efficiency with which genomes can be edited. However, production and screening of gene-edited cell lines remains inefficient. New methods that automate and reduce costs and handling time for the generation and recovery of edited cells would be highly welcome. Our project synergises stem cell biology and cellular genetics expertise (from Horizon Discovery and University of Edinburgh) with novel, single-cell manipulation and microfluidic expertise (from Sphere Fluidics Limited). Both Sphere Fluidics and Horizon Discovery have a track record in bringing valuable products and services to the R&D community. This world-class team will develop and validate a new microfluidic-based device for GE, that enables production of high quality engineered cells in a more rapid, efficient and less costly way. This project will support the development of a new benchtop device that will accelerate medical research and improve production of valuable products such as new therapeutics, foods or fuel sources. It will enable innovation and generate a significant return on investment (>200-fold) and provide major commercial potential for the partners, giving them a global lead in this area and creating new jobs.

The aim of this project is to establish new and innovative approaches for the manufacture of high-value, genome-edited cell lines used in bio-medical research. Genome editing is rapidly becoming an essential tool in all segments of life sciences R&D, from basic research to drug discovery and diagnostics, therapeutics (incl. regenerative medicine), synthetic biology, bio-manufacturing, environmental sciences, AgriTech and food manufacturing. Like DNA sequencing, it is widely expected that genome editing will lead to major changes in multiple industry sectors and result in disruption of global supply chains at multiple levels. This project aims to catalyse this process. The project will harness innovative gene editing technology and automation in cell handling, together with highly parallel, high capacity and data-dense analytical approaches to create a manufacturing platform that enables greater throughput cell creation with integrated cell analysis and characterization capability. This will provide Horizon not only the ability to offer more products at a market-disrupting price, but also at a quality level that comprehensively drives the market towards buying Horizon’s products and away from ‘DIY’. These elements will also combine to establish Horizon as the ‘go-to’ partner for strategic relationships with biopharma companies for the provision of larger scale solutions.

This project will deliver a pipeline of engineered Chinese Hamster Ovary (CHO) cells with characteristics and performance that will enable improved manufacture of novel biologic products. Recent research has identified critical metabolic check points that control CHO cell growth, and characterised pathways controlling product integrity and yield. In this project we will use this knowledge to deliver multiple and combinatorial gene ‘edits’ in CHO cells to produce cells that deliver efficiency and cost gains in manufacturing processes for biotherapeutic products, and broaden the product range that can be manufactured in this system. The improved performance of the cells will be assessed in fermentors and scaled-up to “manufacture ready” processes to ensure that project outputs are translatable into the manufacturing setting and outcomes are widely disseminated to the UK academic and commercial bioprocessing communities.

This project will deliver innovative products that drive the development of enhanced analytical systems to meet the changing needs of diagnosis and stratification of cancer patients. This will allow patients to benefit from recent advances in molecular pathology by delivering more reliable and earlier diagnosis, personalized therapies and disease monitoring to achieve improved outcomes. The project will develop, test and validate materials derived from cell lines that will be engineered to reflect the genetic modifications seen in different cancers. This approach will enable the project partners to produce new and highly innovative reference standards (including formalin fixed paraffin embedded cell blocks and genomic DNA) as well as methods and protocols that can be used in all laboratories to increase efficiency and sensitivity of diagnostic testing and enable standardized, controllable proficiency testing across all geographical locations.

Awaiting Public Project Summary

Awaiting Public Project Summary