Details of Grant 

EPSRC Reference:	EP/C534395/1
Title:	Dendrons for Targeted Gene Therapy
Principal Investigator:	Smith, Professor DK
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Chemistry
Organisation:	University of York
Scheme:	Standard Research (Pre-FEC)
Starts:	01 October 2005	Ends:	30 September 2008	Value (£):	92,422
EPSRC Research Topic Classifications:	Chemical Synthetic Methodology Drug Formulation & Delivery
EPSRC Industrial Sector Classifications:	Healthcare Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Summary on Grant Application Form
The discovery of the double helical structure of DNA is undoubtedly one of the most significant and inspiring scientific advances of the 20th Century. It is now clearly understood that many human diseases are caused by defects in single genes. It is conceptually simple to imagine that by treating a patient with the correct copy of a gene, it may be possible to cure their illness - an approach to medicine often referred to as gene therapy. Although simple in concept, it is actually much more complex to deliver genetic material into cells in a useful form. For this reason, the development of technology to transfer DNA into cells has sparked great interest. This so-called 'transfection' process is of key importance if gene therapy is to be successful in patients.Initial approaches to gene transfection focussed on using viruses, which are well known to carry genetic material into cells. The genetic information within the virus was replaced with the therapeutic gene, and it was hoped that the virus would act as a vector, transporting the DNA into cells. This method works well in vitro, but when applied to patients in vivo has led to unexpected side effects - including death. This is believed to be a consequence of an immune response triggered in the patient by the viral vector. The search for new non-viral DNA delivery agents is therefore of great importance, and a number of these are currently being developed.We have recently produced a series of new molecules with branched (dendritic) structures, which are capable of binding with high affinity to negatively charged species such as phosphates. Most relevantly, these molecules bind DNA (a polyphosphate) with extremely high affinity. The strength with which these new molecules bind DNA is remarkable - highly competitive with the current non-viral DNA delivery vehicles which are used commercially for in vitro applications. We have also demonstrated that, in combination with detergent molecules, these dendrons can transport genetic material into cells - these final studies have been performed in collaboration with the research group of Professor Daniel Pack (University of Illinois - UrbanaChampaign, USA). This collaboration builds on the overlap between our research interests in Nano and Bio-technology and has created a new international multi-disciplinary team with the expertise and facilities to carry out world-class research.In this new proposal, we intend to improve the structure of our initial dendritic molecules in order to provide them with enhanced activity as well as targeting them to particular types of cell. The unique feature of our dendritic vectors is that whilst their branched surface binds to DNA, there is a empty space at the focal point which can be functionalised with almost anything we choose. By attaching a hydrophobic 'greasy' unit, we can improve the ability of the system to self-assemble with DNA and penetrate the cell membrane. By attaching a polar polymer chain we can improve water solubility and also help stabilise the complex with DNA. Finally, by attaching folic acid, we can target the vectors to tumour cells. In the future this would be useful as the dendritic vectors could carry genetic material specifically into tumours which, when expressed, would generate proteins capable of destroying the tumour.In the project, we intend to synthesise the new vectors and fully characterise their ability to bind to DNA here in York. Using techniques such as transmission electron microscopy we will actually be able to visualise the complexes formed on the nanoscale. We will then test the ability of the systems to carry DNA into cells, including tumour cells in collaboration with Prof. Daniel Pack. The project intends to develop new improved vectors for gene therapy, as well as giving us a real insight into the impact our synthetic modifications have on each stage of the gene transfection process.
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Organisation Website:	http://www.york.ac.uk