Objective
Research objectives and content
The objective of my thesis project is to develop efficient techniques for cell targeting by recombinant retroviruses derived from the Moloney murine leukemia virus. These vectors are currently the most widely used in the gene therapy protocols. However, their use is, at the moment, restricted for the genetic modification of dividing cells in culture, to be used in ex vivo protocols. One of the major limitations of the retroviral technology is the lack of cell targeting techniques. The ability to selectively infect predetermined target cells, of high therapeutical value, would open the doors for a number of clinical and basic research applications.
Most importantly:
1) it would improve the current yields of gene delivery in under-represented cell types, like early hematopoietic progenitor cells, thus improving gene therapy efficiency.
2) it would open the possibility for in vivo gene therapy, thus dramatically reducing its COSt and labour required at present
3) it would provide to researchers a valuable tool for creating animal models for human diseases as well as models of carcinogenesis and animal development
4) ability to target tumour cells could be used as a surveillance treatment to prevent metastasis, by delivering +suicide genes, selectively into tumour cells.
My thesis work is based on the modification of the envelope glycoprotein of Moloney murine leukemia retrovirus, which is the principal determinant of the retroviral host range. The modifications to be introduced will be such to enable the recombinant retrovirus to select and infect cells through the recognition of novel cell surface markers. My specific aims will be two-fold. In a first step, I will improve the in vitro cell targeting technology, using cultured cell lines.
This will include:
i) a study for the most suitable site of mini-antibody insertion into the retroviral glycoprotein, by testing envelopes carrying such insertions at various sites, alone or in combinations (our lab has already demonstrated the feasibility of redirecting retroviral specificity through the insertion of an anti-MHC I mini-antibody on the retroviral envelope glycoprotein)
ii) the functional characterization and usage of a new mini-antibody, raised against human MHC II molecules.
iii) the application of the above mentioned technology for the modification of anon-retroviral glycoprotein, namely the Vesicular Stomatitis Virus G protein, known to have many potential advantages in terms of infection as compared to retroviral envelopes.
In a second step, we will turn to the development of an in vivo targeting model involving transgenic mice (human MHC I expressing transgenic mice are already available). To test the specificity of cell targeting in the animal, we will induce cell-type specific tumours, using oncogenic murine retroviruses with modified envelope glycoproteins. This part of the project will benefit from the long-standing expertise of the laboratory in the oncogene field
Training content (objective, benefit and expected impact)
The above research includes training in recombinant retrovirus technology on top of the training in basic molecular biology techniques and mammalian cell culture facilities. The second part of the project will also involve manipulation of animals under standard conditions. As mentioned above, the expected scientific impact is the improvement of current gene therapy protocols together with the development of new tools for basic research applications. Other important benefits include the communication between scientists between the supervision board (A. Papavassiliou et al) in the Medical University of Patras, Greece (where the applicant is registered) and the director of the group and tutor of the thesis (M. Piechaczyk) at the Institut de Génétique Moléculaire, France (where the thesis work is performed), as well as the transfer of know-how back to the applicants home country, Greece (a less-favoured European region) when the applicant returns.
Links with industry / industrial relevance (22)
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 microbiology virology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine oncology leukemia
- natural sciences biological sciences molecular biology
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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
34293 MONTPELLIER
France
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