Public Funding for Oxford Genetics Ltd

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.

Many modern therapeutic treatments require products and drugs that must to be manufactured in human cells for them to work effectively. At present, the human cell based manufacturing industry is dominated by a few standard systems (normally CHO or HEK-293). These systems were first established for research use only, in some cases as far back as 1957 (CHO) and were eventually adapted for large scale manufacture in the late 1980's. Consequently, these systems are far from optimal, and were created at a time when genetic engineering was in its infancy. Hence, there are many areas of potential improvement in these systems that would significantly increase their productivity, also thereby decreasing the manufacturing costs of one the most expensive classes of new drugs. This project aims to take a whole systems approach to optimising these production approaches by improving the DNA that is used to encode the protein drugs, the cell lines used for their production, and develop predictive algorithms that can help to make key strategic decisions before a manufacturing process is initiated e.g. based on the protein drugs sequence, should we expect production problems? And how can these be mitigated before they are encounted in the manufaturing process? This proposal incorporates the state-of-the-art, and a range of innovations that use machine learning, gene editing, DNA analysis, and cell manipulation, to collectively improve the productivity of mammalian biology.

Antibodies are one the most successful treatments for a range of human diseases, including virus and bacterial infections and cancer. They work by binding to other molecules, thereby inactivating them or allow the immune system to clear them from the blood. However, the isolation of antibodies that recognise a specific target remains challenging, significantly reducing progress, particularly for complex cell surface membrane proteins. This is because most methods to generate antibodies use purified proteins, and often these do not share the same shape as the natural protein. Our approach circumvents these issues, providing a simple, rapid and scalable approach for bioselection of lead candidate antibodies. During this project we will demonstrate our technology by generating antibodies against the two valuable targets, including a G protein coupled cell receptors (GPCRs, e.g. DRD1) and also against a cancer immune checkpoint inhibitor (e.g. PD1). Our technology will provide antibodies with many diagnostic, scientific and therapeutic applications. We aim to: (i) Use bioinformatics to produce antibody libraries with greater diversity, (ii) Demonstrate the technology to find antibodies targeting DRD1 and PD1, (iii) Characterise the new antibodies for therapeutic applications.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

Recent advances in the treatment of a range of autoimmune diseases and cancer have required increasingly complex medical solutions. One rapidly expanding range of very successful treatments is the delivery of DNA to human cells (gene therapy) to provide them with new features and properties to help fight disease. A highly efficient method of achieving this is to use modified viruses, such as lentiviruses, to deliver the DNA. However, the process of making lentiviruses is highly inefficient because no cells have yet been made that allow the virus to be packaged efficiently. The reason for this is that some of the genes required to do this are toxic to the cell. We have recently developed a novel solution to this problem, and have already generated a first generation cell line that produces lentiviruses highly efficiently. We now aim to develop clinical grade versions of this cell line and create a series of further, more advanced, cell lines for improved lentivirus production.

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Many different factors influence whether a piece of DNA will work in a biological setting, to express the protein it encodes. Proteins represent a broad new class of exciting but expensive new medicines. Poor DNA activity is particularly problematic when manufacturers of proteins need to produce large quantities by industrial manufacture. At Oxford Genetics we have developed a wide range of tools and expertise to allow us to design and build DNA sequences that produce high amounts of proteins. In this project we aim to industrialise a large proportion of our existing work flow and make the assembly of complex DNA an automated high-throughput process. This will enable the rapid and efficient development of DNA sequences that are optimal for producing proteins in any system, and should lead to major improvements in protein manufacture. This will benefit many aspects of commerce and medicine in the UK.

The production of recombinant proteins for medical research and healthcare is a rapidly expanding area of biotechnology. However, many of these proteins must be manufactured in expensive mammalian systems to ensure correct protein folding, where the yield is typically low in comparison to bacterial systems (usually 100-1000-fold lower). In part this is due to the inferior strength of mammalian promoters (that control protein production) in comparison to bacterial counterparts. At Oxford Genetics Ltd we have developed a ‘bioselection’ cloning system to screen large numbers of recombinant mammalian promoters. We have chosen 5 potent recombinant promoters for further development. In this project we will analyse these 5 promoters in detail, aiming to identify the key features that make them successful, and incorporate multiple such features into a new range of ‘superstrength’ promoters. This will dramatically improve the yields of recombinant proteins during manufacture, making production of recombinant proteins in mammalian cells far more cost effective.

Oxford Genetics is a new biotechnology company that aims to become the UK’s pre-eminent producer of genes and DNA plasmids. The company has been trading for just under one year, and has already established a worldwide market for our DNA products. Genes encode proteins, and in this project we will develop a technology that can ensure the genes customers buy from us work efficiently. A gene is normally represented in biology using a string of letters, A, T, G and C to represent the DNA sequence. The order of these letters contains the information that allows the gene to encode a particular protein. However, the genetic code is highly redundant, and the same protein can be encoded using many different sequences (strings of A, T, G or C) that ‘work’ with different efficiencies. This influences the overall efficiency of gene expression and protein production, making it very difficult to know which particular DNA sequence will be optimal for biological investigation. In this project we will deconvolute this complexity by designing DNA sequences that can be tested side-by-side to enable us to determine which particular DNA base sequences work best in mammalian and bacterial cells. This is a tricky question, as the order of the DNA bases used can have complex effects that may interfere with the efficiency of protein production. We have therefore designed a series of experiments that will enable us to generate a unique algorithm that can applied to all of the genes that we provide to our customers for expression in a particular organism. This provision to our customers will position us a leading DNA provider and instil confidence to customers using our sequences.

The production of recombinant proteins for medical research and healthcare is a rapidly expanding area of biotechnology. However, many of these proteins must be manufactured in expensive mammalian systems to ensure correct protein folding, where the yield is typically low in comparison to bacterial systems (usually 100-1000-fold lower). In part this is due to the inferior strength of mammalian promoters (that control protein production) in comparison to bacterial counterparts. The strength of bacterial promoters is easy to predict, and the amount of protein produced is often proportional to how similar the promoter used is to the ‘optimal’ consensus promoter. In mammalian promoters, these same predictions cannot be made because the structures are much more complex, making it difficult to know which sections of the promoter might enhance protein production. As a result, most mammalian expression systems are based on naturally-occurring ‘wild-type’ promoters, which have actually evolved for physiological functions, not commercial protein manufacture. Our preliminary data show that significantly stronger promoters can be developed using our technology, with significant implications for protein manufacture. At Oxford Genetics Ltd we have developed a ‘bioselection’ cloning system called ‘Prometheus’ to screen large numbers (>4000) of recombinant mammalian promoters. The technique allows a wide array of strong ‘wild-type’ mammalian promoters to be ‘shuffled’ and screened to identify new composite promoters that produce more protein than the current gold standards, CMV and CAG. Preliminary results are exciting, and in this project we aim to develop ‘superstrength’ promoters that will dramatically improve the productivity of transgenes, including proteins and antibodies for manufacture.

Modern biological and medical research is highly dependent on genetic engineering (i.e. the modification of Deoxyribose Nucleic Acid, DNA). DNA is the molecule that encodes all of the genes which make an individual organism. Its modification has revolutionised biomedical research, particularly in the fields of vaccinology, oncology, immunology and microbiology. For most research purposes DNA needs to be engineered in order to be useful. The established method of genetic engineering involves obtaining a 'backbone' piece of DNA and then designing strategies to modify it with enzymes and join it to other pieces of DNA to suit the needs of the particular research project. This is a complex and laborious task, and if the direction of the research changes it is often difficult to change the DNA construct to have a new functionality, without purchasing a new 'backbone' and starting the process from scratch. Oxford Genetics intends to develop the world’s most flexible and innovative genetic engineering platform that allows scientists to sequentially modify their DNA constructs to suit their emerging research needs. By using a 'cassette' system, pieces of DNA can be easily changed, allowing simple production of desired constructs without having to start again. This ‘genetic Lego’ will make a major saving to research budgets and accelerate the work of scientists by giving them access to hundreds of ready-made DNA cassettes that can easily slot into their constructs. As such, the company’s business strategy is based on a bait and hook model. Our system will have multiple advantages over our competitors and no other biotechnology company has yet taken this approach to genetic engineering. Oxford Genetics believes it can introduce a step-change in genetic engineering technologies, providing more efficient, cheaper and easier to use DNA, and can capture a substantial share of a very large and expanding market.