Objective
This project will combine state-of-art synthetic polymer chemistry with cell biology in design and development of efficient vectors for delivery of genes into target cells in vitro and in vivo. This is opportune because the potential usefulness of genetic modification, involving applications ranging from in vitro transfection to clinical gene therapy of human diseases, are now frequently limited by poor efficiency and selectivity of gene delivery and expression.
These novel vectors will be completely synthetic, hence they will be fully defined and developed throughout for safety and efficiency. They are designed for generic applicability, self-assembling with any DNA expression vector and capable of incorporating any targeting agent. Ease of scale-up production will make them easy to produce and well suited for routine application in the laboratory as well as clinically for targeted gene therapy of many diseases.
This interdisciplinary project represents a coalescence of expertise from cell and molecular biologists and polymer chemists, all with expertise in the field of targeted drug delivery. The best aspects of liposomal and polymer-based delivery systems are combined, designed and developed within the broad context of cellular and molecular biology. The system will be designed for simplicity of application, and the vectors will self-assemble with DNA to permit routine widespread use. Considerable preliminary data are described which establish the feasibility of the approach and suggest the possibility of important progress.
The new vectors will be based on soluble synthetic polymers, designed to interact with DNA expression vectors and condense them to a very small size (< 35 nm diameter). The resulting nanoparticles will be packaged within a hydrophilic coating to improve biocompatibility, and biotin groups incorporated onto the external surface will permit versatile attachment of streptavidin-conjugated targeting agents.
On arrival at the target site the vectors will bind cell surface receptors and trigger endocytic internalisation. The falling pH will induce shedding of the hydrophilic coating and activate a fusogenic function, locally permeabilising the wall of the endosome. The polymer- DNA complex will then be released into the cytoplasm, and nuclear-homing sequences linked to its surface will promote nuclear accumulation ar enhanced transfection efficiency. The whole process is shown schematically in Figure 1.
The polymer chemists will define the chemistry of the polymers and block copolymers, constructing materials with required physicochemistry and devising linkages with appropriate degradation characteristicsthe pharmaceutical scientists will assemble the components, characterising and refining the complexes with particular emphasis on triggered membrane activity. Cell biologists will evaluate biocompatibilitylcytotoxicity and stability, cell targeting and internalisation, intracellular distribution and efficiency of transfection.
Development work will be performed with reporter genes and constitutive promote but therapeutic efficacy will ultimately be assessed using a tissue-specific promoter sequence to control expression of a therapeutic construct (Section 2.5 combining two targeting strategies for reinforced selectivity of gene activatio
At the end of this 3 year project we aim to have achieved efficient targeted transfection of ceils in vitro, and to be ready to commence clinical evaluation It is likely that cancer will provide the first testing ground due to inadequat treatments available for that disease. The co-ordinator is working within a medicoscientific centre actively developing new genetic approaches to clinical cancer treatment, using traditional vectors, and the novel delivery system will be developed within this environment, ensuring thorough and responsible clinical evaluation when it is appropriate. Having established safety in cancer patients we plan to extend the use of the vector to other diseases such as Iysosomal storage diseases and AIDS.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- natural sciences biological sciences genetics DNA
- natural sciences chemical sciences polymer sciences
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- medical and health sciences clinical medicine oncology
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
B15 2TJ Birmingham
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.