Team:SupBiotech-Paris/Gene therapies




Gene therapy [1]

Gene therapy consists in delivering specifically a gene in target cells or tissues with a minimal of toxicity. Swap a defective gene with a healthy gene to restore the lost function in a patient is the principle of this therapy. Gene therapy represents a promising tool for some diseases treatment and principally for cancer: nucleic acids administration can induce or inhibit the production of a specific protein to induce a therapeutic response.
Unlike medicines which act on the activity and function of a protein, therapeutic genes act more upstream, at the dysfunction source.

Administration mode [2]

Genes can be delivered ex vivo or in vivo. Ex vivo cells are removed from patient tissue, and exposed to the gene-medicine. Transgenic cells are selected, and then reintroduced into the patients' organism. Gene can be delivered in vivo as well: DNA is directly injected into a patient, usually in the tissue to treat, to increase transfer efficiency. This simple protocol presents the advantage to do not require surgical intervention.

However, ex vivo administration is still the technique the most used, like attest the current number of clinical trials.

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Gene therapy and challenges [1,3]

Gene therapy faces several problematic which reduce its efficacy on humans:

- To identify mutations responsible for the disease,
- To identify healthy genes,
- To deliver the gene-medicine to the target cell.
- To optimize the gene-medicine expression.

Identifying the target gene requires answering to several questions: Which gene is found in the disease signalization pathway? Is this gene expressed at the beginning or in the final phase of the disease expression? Indeed, the target gene inhibition can be not sufficient enough to inhibit the disease expression.

So, for cancer treatment, there are many target genes and strategies: the tumor suppressor p53, the oncogene inhibition with antisens of oligonucleotide, ribozymes and siRNA use.

Indeed, cancer can be the result of DNA damage due to carcinogens or appear spontaneously during DNA replication. The inability to correct this mistake due to mutation of gene repairing or to the absence of gene control to the cell cycle can give a growth advantage to the cell. These genes constitute the best targets for gene therapy in cancer treatment.

When genes are identified, gene therapy success depends on the efficiency of the gene transfer in the cell. Transport of gene-medicine is one of the most difficult challenge encountered by gene therapy. The efficient transfer system which stabilizes, induces and express transgene has not been found yet. Naked gene-medicine transfer in cells is still not very efficient. The gene-medicine expression is as low in intensity as in time because of the polyanionic nature of the DNA which not permits to pass through the cell membrane barrier. Thus, 100 000 DNA molecules should be necessary by target cell to permit at least to one DNA sequence to penetrate in the nucleus. To this is added the non efficiency of the naked medicine transfer. Indeed, the naked DNA use decreases the target efficacy to a given tissue, so the number of cell which has incorporated the gene-medicine still low. But the pharmaceutical industries objective is the systemic administration of these genes.

One of the solutions consists to integer DNA in a vector. This last one should reply to several criteria:

- Be able to protect DNA,
- Target the desired cell with a high specificity,
- Deliver easily the gene through the cell membrane,
- Deliver the gene to the nucleus to permit its expression.

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In conclusion...

... Gene therapy made its proof for monogenic diseases treatment, like hemophilia, or for cancers. Moreover, molecular and cellular biology evolution combined to bioinformatics progresses permits to the gene therapy concept to be even more promising… However, this tool should be further optimized, in particular in the gene-medicine transport. Despite researches abundance on this subject, an efficient vector has not been discovered yet.

Gene therapy success stays in the capacity to transport the gene in the target cell and to obtain a high expression level. It appears necessary to design a new vector.

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