Creating Treatment Based on the Genome

Genome-driven therapy is based on the introduction of functional genes into somatic cells to correct genetic defects or exert a therapeutic effect. The number of patients that have been benefit from GDCT in the US  increased from approximately 29000 of 500000 patients (5.8%) with metastatic cancer in 2006 to 51000 of 564830 (9.02%) in 2018, and the proportion of patients with cancer who benefited went up from 0.70% on 2006 to almost 5% on 2018 (1).

Genome driven therapy was developed for the treatment of genetic diseases, but today this therapy is showing success for other conditions with certain inclusion criteria: I.e. lethal disease without treatment caused by a single gene. the regulation of this gene has to be well defined.

Genome driven Therapy Against Cancer

The transformation of a healthy cell to a malignant one is a sequential process by which a cell acquires new characteristics that allow it to proliferate uncontrollably and ispread through the organ or origin and to elsewhere in the body (metastasis). These characteristics can be targets for the design of therapies that eliminate tumor cells, improve the immune response, or block tumor proliferation. The elimination of tumoral cells can be carried out correction of tumor suppressor genes or inhibition of activated oncogenes; suicide gene therapy (infection of the tumor with a selective replication virus that encodes an enzyme capable of activating a prodrug in the tumor) and oncolytic therapy (infection of tumor cells with a lytic virus). The host’s immune response can be enhanced by immuno-potentiating therapy (which increases tumor immunogenicity or enhances the antitumor activity of cells of the immune system), and the proliferation of tumor cells can be inhibited by antiangiogenesis therapy(2).

The Pathways

The most efficient delivery system for gene transfer to cancer cells in vivo is adenovirus-based. Viruses possess desirable biological characteristics like the tendency to transfer and express the therapeutic gene in quiescent cells; they are easy to handle and propagate in vitro; they are not integrated into the cell genome, and they have a lytic life cycle. Additionally, they induce an immune response in vivo which potentiates antitumor immunity and allows fast elimination of the vector, guaranteeing a short-term antitumor effect that protects healthy cells from prolonged exposure to toxic products. (3).

When a virus transfers genetic material into the cell interior, the process is called transduction or infection, and the therapeutic gene is called a transgene (4).

Although non-viral systems for gene transfer into the cell interior have some advantages, viral systems are more widely used in clinical trials because of their small size, the protein capsid that protects the therapeutic gene from enzymatic degradation, and its efficient internalization mechanisms. The viruses most commonly used in gene therapy include members of the Retroviridae (gammaretrovirus and lentivirus) families, Adenoviridae, and Herpesviridae (HSV) 19, and Parvoviridae (adeno-associated virus) (5).

Viral gene transfer can be done in vivo or ex vivo. In vivo involves gene transfer within the body. This method is easy to employ in the clinic, but the targeting is not precise and the transduction efficiency is very low. Ex vivo involves the removal of host cells, their genetic modification in vitro, and their reimplantation into the original tissue. This is the method of choice for protocols that use dendritic cells, or CD34 + cells because it guarantees the specificity of the target and allows researchers to quantify the efficiency of transduction (6).

The obstacles that impede the clinical success of gene therapy have to do more with the tools than with the idea behind gene therapy. The expression of the transgene is essential for a gene therapy strategy to be effective. The level of expression of genes transduced into somatic cells fallss after a short period or is maintained inconsistently.

Another big barrier is the ability to deliver the transgene to the target cell, especially for the treatment of cancer. In most cases the vectors can transduce only a small minority of cells when administered intratumorally and are not effective in reaching tumor cells when administered systemically. This limitation can be partially overcome by gene therapy agents that induce a strong neighborhood effect, such as prodrug activation or gene immunotherapy (3, 7).


In general, the factors necessary to make gene therapy effective against cancer are no different than for other new therapeutic modalities. They include technical factors (distribution and gene expression), clinical factors (therapeutic efficacy and safety), and socioeconomic factors.


1. Marquart J, Chen EY, Prasad V. Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology. JAMA oncology. 2018;4(8):1093-8.

2. Hyman DM, Taylor BS, Baselga J. Implementing genome-driven oncology. Cell. 2017;168(4):584-99.

3. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nature Reviews Genetics. 2003;4(5):346-58.

4. Guo ZS, Li Q, Bartlett DL, Yang JY, Fang B. Gene transfer: the challenge of regulated gene expression. Trends in molecular medicine. 2008;14(9):410-8.

5. Silva G, Poirot L, Galetto R, Smith J, Montoya G, Duchateau P, et al. Meganucleases and other tools for targeted genome engineering: perspectives and challenges for gene therapy. Current gene therapy. 2011;11(1):11-27.

6. Temme A, Morgenroth A, Schmitz M, Weigle B, Rohayem J, Lindemann D, et al. Efficient transduction and long-term retroviral expression of the melanoma-associated tumor antigen tyrosinase in CD34+ cord blood-derived dendritic cells. Gene therapy. 2002;9(22):1551-60.

7. McCarthy JJ, McLeod HL, Ginsburg GS. Genomic medicine: a decade of successes, challenges, and opportunities. Science translational medicine. 2013;5(189):189sr4-sr4.