Cancer and Gene Therapy

By Wei Yi Ooi

DNA or deoxyribonucleic acid is known as the universal basic unit of life. It is a double stranded, complementary polynucleotide molecule intertwined together in an antiparallel manner, forming a double helix. The nucleotide sequences in DNA provide the genetic information needed for biological functions of growth, development and reproduction of almost all known organisms, including humans and various viruses. In humans, the approximate number of DNA bases is around 3 billion and the human genome is packed and organized into the 23 pairs of chromosomes in the nucleus of each cell in the human body (Annunziato, A. 2008).

Mutations are the lead known cause of cancer and a mutation refers to the alteration of nucleotide sequence in DNA, when exposed to ionizing radiation such as higher-energy ultraviolet rays. Examples of mutagenic chemical substances that lead to point mutations in DNA include Ethyl methanesulfonate and N-methyl-N-nitrosourea (Lidder et al., 2012).

 Various classes of mutation give rise to different effects on protein structure. For instance, missense mutations occur when substitution of a single nucleotide takes place, causing a different codon- which codes for a different amino acid. A frameshift mutation is another class of mutation where either an insertion or deletion of a base occurs – this alters the entire sequence from the point of mutation.

 Frameshift mutations induce extreme changes in the coding sequence of a protein and consequently, they have a high chance of changing the three-dimensional structure of a protein, and thereby the function of the protein. The chance of inducing genetic disorders such as cancer is generally increased by two factors: increasing the number of genes mutated, and the presence of mutations in oncogenes and tumour suppressor genes.

An important example of a tumor suppressor gene is the TP53 gene that encodes the tumor suppressor protein known as p53. The protein plays a significant role in regulating cell replication, and inhibiting the development of tumors caused by unsuppressed cell proliferation. The mechanism of the p53 protein involves determining whether cells with damaged DNA will undergo programmed cell death (apoptosis) or whether the cell will repair its DNA. More than 50% of diagnosed cancers are believed to be a result of mutations in the TP53 gene (Olivier et al., 1998). The mutation in the TP53 gene itself is often a missense or point mutation, which refers to a single base substitution that results in the production of a different protein (Rivlin et al., 2018). This results in the altered p53 protein failing to carry out its normal function of regulating the cell cycle and its capabilities of acting as a tumour suppressor.

Gene therapy is a modern approach in the medical field which involves the administration of foreign genetic material to the nucleus of the target cancerous cells, in order to induce self-destruction and halt the uncontrollable proliferation of the cancerous cells. It aims to compensate for mutated, abnormal genes and produce the proteins required for healthy growth of cells (Abbas et al., 2018).


Researchers have developed several ways to introduce therapeutic genes into the human body. The delivery of foreign transgenes can be mediated by viral vectors or non-viral vectors. A viral vector that is commonly used in the administration of transgenes is the retrovirus, due its ability to integrate into host cells (Bouard et al., 2009). The integration process involves replacing the essential viral genetic material with the desired genetic information. The engineered retrovirus is then introduced into the body, with their genetic material (including the desired genes) integrated into the chromosome of the targeted body cells. With retroviral gene therapy, there is an advantage in the ease in which the preparation of the recombinant virus can be achieved. However, some concerns have also been raised, such as the possibility of random integration into the host chromosome, which may result in insertional mutagenesis or activation of oncogene, causing further unpredictable genetic damage (Baum et al., 2004).

On the other hand, liposomes are non-viral vectors composed of phospholipid bilayers that form a spherical vesicle with the ability to encapsulate drugs. The cell- membrane-like structure of liposomes is a key feature contributing to its ability to protect liposomic cargo from dilution and enzyme degradation within the blood circulation system (Sercombe et al., 2015).

Non-viral vectors such as these are frequently used in the delivery of molecular cargo such as artificially modified DNA, to achieve a therapeutic effect on target body cells. Unlike viral vectors, liposome vectors can be engineered to ensure site-specific targeted delivery via specified targeting receptors, reducing the exposure of a transgene or anticancer drug to normal cells (Lee, et al., 2017). Additionally, due to the high demand of fats needed for rapid growth of cancerous cells, liposomes (with encapsulated transgenes or drugs) can be easily recognized as a source of lipid- encouraging the absorption of liposomes by cancer cells and promoting the release of anti-cancer drugs into the cell cytoplasm.

Currently, gene therapy is still regarded as a new concept under active research. However, through increasingly successful therapy treatment in the past decade, it has become evident that the therapy has great potential in improving the prospects of patients suffering from genetic disorders. Moving forward, there has been a growing sector of gene therapy that looks to prevent genetic disorders rather than treat pre-existing conditions. Such practices will require a great deal of further scientific development, however scientists are confident gene therapy holds great promise and will grow to become a game-changer in the future medical field.

References:

Annunziato, A. (2008) DNA Packaging: Nucleosomes and Chromatin. Nature Education 1(1):26. Available from: https://www.nature.com/scitable/topicpage/dna-packaging-nucleosomes-and-chromatin-310/ 

Preetmoninder Lidder, Andrea Sonnino (2012) Biotechnologies for the Management of Genetic Resources for Food and Agriculture. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/chemical-mutagen

Magali OlivierMonica Hollstein, and  Pierre Hainaut (2010). TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Available from: doi: 10.1101/cshperspect.a001008

Noa Rivlin, Ran BroshMoshe Oren, and  Varda Rotter (2011) Mutations in the p53 Tumor Suppressor Gene 2(4): 466–474. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135636/

Zaigham Abbas and Sakina Rehman (2018) An Overview of Cancer Treatment Modalities. Available from: DOI: 10.5772/intechopen.76558

D BouardN Alazard-Dany, and  F-L Cosset (2009) Viral vectors: from virology to transgene expression 157(2): 153–165. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629647/

Christopher Baum, Christof von Kalle (2004) Molecular Therapy 9(1):5-13. Available from: DOI: 10.1016/j.ymthe.2003.10.013

Lisa Sercombe, Tejaswi Veerati, Fatemeh Moheimani, Sherry Y. Wu, Anil K. Sood and Susan Hua (2015) Advances and Challenges of Liposome Assisted Drug Delivery 6: 286. Available from: doi: 10.3389/fphar.2015.00286

Y. Lee, et al. (2017) ‘Stimuli-Responsive Liposomes for Drug Delivery’, Wiley Interdiscip Rev Namomed Nanobiotechnol 2017. Available from: https://www.creative-biogene.com/services/liposomes-in-gene-therapy.html

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