From 2009.igem.org

Latest revision as of 03:23, 21 October 2009

Project

Introduction Current therapies Gene therapies DVS Concept Tissue Vector Cell Vector Therapeutic plasmid Conclusion Implementation Tissue targeting Antitumor action Treatment modeling Conclusion

Ressources

BioBricks Material & Method Bibliography

Ethics & Safety

Ethics Safety

Conclusion

Vectorization encounters several problematic like stability, toxicity, targeting, resistance or stealth to the immune system, passage through the membrane and industrialization.
The Double Vector System (DVS) offers a key to these major problematic.
DVS is composed by a first vector, tissue vector, from bacterial type, able to reach a tissue and by a second vector, from phage type, able to reach a target cell. When the target cell is reached, it releases a therapeutic plasmid which has an action against the disease.

The first vector : Mycobacterium avium, goes to the tissue of interest for which it has a high affinity. It resists to the immune system thanks to its cell wall and has a low toxicity for its host. In the target tissue, it creates the second vector, the cell vector.
The cell vector targets the cell type of interest, which increase the DVS specificity. The cell vector integer itself in target cell, thanks to viral proteins exposed to its capsid. These proteins permit it to be efficient and offer the capacity to pass through eukaryotic cell membrane. The cell vector is able to encapsidate the therapeutic plasmid and to deliver it after its own internalization.
The therapeutic plasmid expresses one or more therapeutic genes replying to target physiopathology. It possesses a sequence providing its encapsidation in the cell vector, and a DTS sequence (DNA nuclear targeting sequence) to its transport inside target cell nucleus.

DVS improves underlying vectorization problematic. Tissue vector characteristics bring a solution to specificity issue and to elimination by the immune system met by vectors. Cell vector characteristics reinforce the vector specificity and give a solution to pass through the cell membrane and to the therapeutic agent delivery.
DVS becomes one of the more specific vectors by permitting the transport of one or more gene insert in a therapeutic goal with a high efficiency.

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DVS application

Gene therapy actually permits to treat several pathologies. DVS is a new tool to integer a gene insert in a target cell. We choose to use DVS in lung cancer.
Nowadays, lung cancer is the most spread cancer. Often associated to tobacco, it can touch people who had never smoked as well.

Lung cancer can be divided into several types :

In each case, like in most cancers, tumor suppressor genes are mutated and become non functional. DVS bring tumor suppressor genes « wild type » and their promoter in cancer cell of the lung.
Lung cancer has been chosen in consequence of the natural tropism of the tissue vector, Mycobacterium avium, for lung. Inside the lung, it delivers the cell vector. These one infects cells. In the case of healthy cells, tumor suppressor gene promoters are naturally present but not activated. Therapeutic plasmid promoters will not be activated as well, so there is not apoptosis induction. But in the case of tumor cells, tumor suppressor gene promoters are activated but their sequence are mutated so proteins are not functional and the apoptotic pathway is not induced. Therapeutic plasmid brings a new sequence of these tumor suppressor genes with their promoters. These promoters are activated and new transcript proteins are functional and able to induce the apoptotic pathway of the cell.

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Future prospects

DVS is a tool usable in several diseases. It can be adapted to pathologies by the strategic choice of the tissue vector. In function of the tropism of the bacterial strain chosen, different organs are reached. Furthermore, DVS is specific thanks to the therapeutic plasmid which contains interchangeable genetic sequences depending of the target disease.

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