Objective
Intracellular immunization refers to the use of strategies to interfere with the function of intra- or extracellular gene products in animal cells. Intracellular immunization approaches are receiving great attention for application to human gene therapy and for functional genomics, and include antisense RNA or oligonucleotides, ribozymes, dominant negative mutants. Each of these approaches suffers from drawbacks and limitations. This proposal is about applications of a new strategy for phenotypic knockout in mammalian cells: intracellular antibodies.
This new strategy for intracellular immunization in animal cells, based on the ectopic expression of recombinant antibodies and their targeting to different subcellular compartments, was developed by some of the scientists involved in this project and successfully applied in a variety of systems, including animal and plant cells. The intracellular antibody approach combines the richness of the virtually unlimited repertoire of the immune system to the versatility provided by the use of intracellular targeting signals. Due to its successes, the use of cloned antibodies for intracellular immunization is likely to become a widely used strategy to inhibit the function of recognised molecules, both for scientific therapeutic and applicative purposes.
The final objectives of the present proposal are to apply the intracellular antibody strategy to block the function of proteins involved in i) the afferent and efferent phases of HIV viral infection and in ii) the (dis)regulation of growth control of mammalian cells, in a perspective of developing gene therapeutical approaches for cancer and restenosis. The work will also involve the refinement and optimization of the intracellular immunization strategy.
Gene therapy for the treatment of HIV-1 infection and AIDS has captured the increasing attention of a number of investigators as an attractive alternative to conventional pharmacological therapies, because alteration of the host cell could potentially confer permanent suppression of viral replication after infection or perhaps even lasting protection against viral infection. Intracellular antibodies are a recent and very promising addition to the panel of intracellular immunization strategies being proposed to treat infectious disease and this project will pursue this, by comparing the efficacy of a panel of antibodies against HIV viral proteins.
With the advance in the molecular understanding of disease processes, it has been appreciated that many diseases result from the malfunctions of signaling pathways. This has led to the development of therapeutical concepts based on the interception of cellular signaling. The manipulation of signal transduction pathways for the control of cell proliferation in cancer and in restenosis by intracellularly expresses antibodies will be a main focus of this proposal.
Lead antibodies derived by the core group are already available in recombinant form and, in some cases, proof of principle for their efficacy as intracellularly expressed proteins, in in-vitro systems, has been provided by partner groups in this core proposal. These lead antibodies will be improved in a rational (structure-based) and irrational (library-based and selection approaches) basis. The intracellular targeting of the antibodies will be further refined, to improve their efficacy. In the case of HIV viral proteins, this will include the incorporation of the antibodies in the viral particles (capsid-targeted viral inactivation). New antibodies will be derived and assessed in cellular intracellular antibody expression systems, for their prospective use in gene therapy.
It is anticipated that an important outcome of the present project will be to provide strong justifications for proposing Phase I clinical trials to determine the safety and efficacy of ex vivo intracellular -antibody based gene therapy for the treatment of HIV infection, forms of cancer or restenosis.
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
- medical and health sciences basic medicine immunology immunisation
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences health sciences infectious diseases RNA viruses HIV
- medical and health sciences clinical medicine oncology
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Coordinator
34013 Trieste
Italy
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