Award details

Refinement and assessment of a novel adenovirus targeting platform for application to human gene therapy

Reference	BB/I005927/1
Principal Investigator / Supervisor	Professor Andrew Baker
Co-Investigators / Co-Supervisors	Professor Stuart Nicklin
Institution	University of Glasgow
Department	BHF Cardiovascular Research Centre
Funding type	Research
Value (£)	383,092
Status	Completed
Type	Research Grant
Start date	04/04/2011
End date	28/02/2015
Duration	47 months

Abstract

The research from our group involving adenovirus-based vectors over the last 4-5 years has principally been focused on increasing our understanding of how the virus uses host factors for cell infectivity in vivo. This has resulted in the discovery of a major new pathway that leads to gene transfer of the liver and spleen following intravascular injection of virus - this is the nM affinity FX binding pathway that we have published on progressively in papers in Cell, Blood and J Virology. We maintain our direction on understanding this interaction through existing grant funding (until 2012) by crystallisation studies, infectivity studies and improving knowledge relating to the FX:HSPG interaction. Based on this success and novelty, we are now in a position to develop a programme of work directly assessing the capacity of this vector platform for in vitro and in vivo targeting of adenovirus. This has been a major impetus in the field but also a very difficult agenda since some critical aspects of virus interaction remained unknown until recently (e.g. the FX interaction and CAR binding on erythrocytes). In this project grant, that is a timely continuation of a previous project (due to end late 2010 that has generated the novel platform we will now exploit) where we will broadly assess this adenoviral vector for targeted gene delivery. We will first refine the platform to include additional capsid modifications to ablate CAR binding and the RGD motif in the penton base to reduce in vivo toxicity and fully assess such vectors in vivo. We will then genetically engineer the virus to include targeting motifs that we believe are the most promising and assess them in vitro and in vivo in a series of well planned experiments for application to cancer cell, renal and pulmonary targeting. The ability to develop this project through BBSRC funding will have an important effect on the field since we possess an international profile that will maintain our research at the forefront.

Summary

Gene therapy is rapidly developing into an effective method to cure or halt the progression of many human diseases. The first gene therapy products have been licensed recently in China (for cancer therapy). Therefore, the use of genes to treat human disease is a realistic opportunity to provide efficient and lasting therapies, especially those diseases that lack optimal drug-based therapies. An absolutely critical aspect of gene therapy is gene delivery, i.e. the method that is used to deliver the therapeutic cargo to the correct cells and tissues in the body. Gene delivery is achieved by a 'vector' that has the capability of transferring the therapeutic DNA into cells - these vectors can either be non-viral or viral-based. Adenovirus vectors are commonly used as a viral-based delivery system and are currently utilised in some 25% of all ongoing clinical trials in gene therapy. The advantages of these viruses is that they have the ability to transfer genes to a broad range of cells, hence this makes them suitable for a wide range of applications to gene therapy. The research from our group has made an impact recently through the discovery that the adenovirus uses a protein that circulates in the blood of the host to infect cells within the host. That is, when the virus is injected into the bloodstream, the virus interacts with a protein in the blood called coagulation factor X. This interaction is very rapid and strong and allows the virus to bind to receptors expressed in the liver. This is the reason why the virus has such a strong ability to transfer genes into liver cells. This is not always useful since we would like to target the virus to cells other than liver cells (such as cancer cells, cells in the lung and cells in the kidney). We have now (through funding from the BBSRC that ends in late 2010) developed an adenovirus that has its ability to bind to coagulation factor X completely removed. This eliminates gene transfer to the liver upon injection of the modified virus into the bloodstream. We now wish to apply for funding to further develop this work and ask whether the virus can now be efficiently targeted to those cells types that are of interest for potential new therapies. We will utilise this grant to refine the virus and include 'targeting systems' for each cell type and test the ability of each system to target using suitable cells and models. We expect that our work will have broad appeal to the gene therapy communuity and have an impact on development and refinement of this virus for future clinical applications.

Impact Summary

We have provided an uploaded impact plan that underscores our commitment to maximising the potential of our research. Additional information as requested is provided below. Beneficiaries (non-academic): - Biotechnology industry. The development of adenovirus has clear potential and modulation of mechanisms that dictate infectivity will be important for any organisation working with these vectors, either as gene therapy agents or as vaccines. Clear developments in vector technology based on hexon mutagenesis are sought. Additionally, this has serious implications in the vaccine field since Ad5 hexon mutants are currently being pursued in the clinical setting. A number of companies are developing adenoviruses in different contexts (e.g. Onco Therapeutics, Crucell, Hybrid systems). The field still requires development of novel platforms for application to gene therapy and this is what we are striving to do. - Policy makers. The use of such technology is governed by MHRA/GTAC and nominated L-RECs in the UK. New technology requires interaction with such agencies if clinical translation is appropriate. Gene therapy is often in the press (in recent times for many strong and positive developments) and this has an impact on the public, funders and policy makers in the long term. Relevance to beneficiaries If successful, our research would have tremendous impact on health since we strive to optimize understanding of adenoviruses and development of platforms for gene therapy in the broad sense (i.e. to different diseases). The University of Glasgow patented the use of FX/hexon interaction and we are striving to exploit such platforms for gene therapeutics through development of targeting systems. This will clearly have benefit to health and reduction in burden on the NHS if successful. This will clearly impact on quality of life to recipients of novel therapies should overall efficacy be above current standard of care. This is the long term view. However, we propose that this research will lead quickly to efficacy studies in animal models (extra 2 years) and then through to regulatory applications and clinical translation (3 years). Each of these steps is dependent on the former. As a member of GTAC, Baker is well aware of the timescales and regulatory requirements for transition of gene therapy into the clinical arena. We are in the development phase. The latter phases clearly will require large teams of scientists, nurses, clinicians, pharmacists etc. thus bring interaction of the work in broader terms in the healthcare sector. What will be done to ensure that they benefit from this research? This is very dependent on the success of the research and the impact and novelty they have. We envisage at early stages interaction in the scientific community through publications and conference presentations. At the same time we will be developing commercialization plans with the Research and Enterprise Office at the University of Glasgow. We have in place collaboration agreements based around the adenovirus/FX patent. In this proposal we do not need additional agreements at all. We therefore have the experience and knowledge to develop this work on an academic level very efficiently and this is also true for the commercialization aspects as we have in the past. Our interactions with industry are strong and Baker has recently co-coordinated a Marie Curie Training Network application through FP7 that involved 2 SMEs and 1 large company centred around adenovirus exploitation for benefit to industry and healthcare (finding decision Spring 2010).

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Microbiology, Pharmaceuticals, Structural Biology, Technology and Methods Development
Research Priority	Nanotechnology
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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