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BLOG: How CRISPR is guiding our way to find new method of treating cancers

Cancer is the second leading cause of death globally. In 2015, there were 8.8 million reported deaths related to cancer.[1] Therapies based on gene-editing have been developed, but high costs drive a need for better and more accessible treatment.

Researchers at the West China Hospital in Chengdu have been developing a new way of treating lung cancers using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) genome editing, with the first clinical trial carried out in October 2016.[2] This treatment method disables a gene called PD-1 (programmed cell death protein 1) in immune cells that are taken out of the blood of a patient with lung cancer. After the gene is deactivated, it is then returned to the body of the patient.[2][3]

Current gene-editing cell therapies available to treat cancers are expensive and time consuming. For example, medics in California have used enzymes called zinc-finger nucleases to cut the DNA of a patient suffering from Hunter’s syndrome and, later on, insert the corrective gene back into the patient.[4][5] Although the patient trial was successful, this gene-editing method is very expensive and much more difficult to engineer than the new CRISPR system. In fact, the zinc finger would cost more than US$5,000 to order, whereas the total cost of CRISPR is only $30.[6]

The high costs of current gene-editing treatments for cancer have made them inaccessible to low-income countries. Indeed, a fact sheet from the World Health Organisation states that ‘in 2015, only 35% of low-income countries reported having pathology services generally available in the public sector’.[1] The discovery and development of CRISPR gene-editing can potentially make gene therapies for cancers available to millions of people from low-income countries.

Another conventional genome editing treatment acknowledged in the past is chimeric antigen receptor (CAR) T-cell therapy, which is most extensively investigated in patients with B-cell malignancies. The basic principle of this treatment is to attach deactivated retroviruses to the patient cells, and then introduce a genetic material which encodes the CAR into the patient DNA and permanently integrates into the genome of the patient cells. Later on, the cells will start to replicate, with the CAR expression maintained, and grow into large numbers. Finally, the large number of manipulated T cells are inserted back into the patient’s blood.[7] Dozens of CAR-T trials are already underway around the world, and clinical trials have shown incredible results.

The approach still demonstrates some drawbacks, however. For instance, people can only be treated with their own modified immune cells, as there are risks of the body attacking unknown T-cells that enter the body. Additionally, this is a long process and we haven’t yet found a way to apply it to a large number of populations. Furthermore, the world regulations on this type of treatment remain unclear and one treatment can cost up to thousands of pounds. In addition, some researchers have found that the CRISPR system allows a more precise and accurate placement of genes, as it is programmable. In an experiment testing two CAR T-cells in mouse models of leukemia, the ones that were inserted via CRISPR have killed more tumour cells than those that were inserted randomly with a retrovirus.[8]

In comparison with current treatments, gene therapies using CRISPR are much cheaper and easier to prepare. The CRISPR system includes two parts: the first part is a strand called RNA, which is an exact copy of the DNA molecule that matches up with a particular site of DNA inside a targeted body cell; the second part is a protein produced by the body called Cas 9, which act as ‘molecular scissors’ to cut the targeted DNA. The RNA acts as a guide that lead the Cas 9 to the targeted DNA molecule and allows it to edit the gene at the particular site.

Like all other gene-editing techniques, there are technical concerns over CRISPR methods. One key concern is that it might miss the target gene, or affect other genes. DNA has a very complex structure and genes are intricately linked, so modifications to the genome can inadvertently affect the function of other untargeted genes and molecules.[9] Target gene selectivity and impact on untargeted genes are therefore the key concerns in the development of CRISPR systems. If these issues are resolved, CRISPR can potentially open up new ways to treat and analyse other type of cancers.

In conclusion, the discovery of the CRISPR method and its success in some clinical trials has proved its accuracy at targeting DNA molecules. Additionally, it can be easily engineered in any lab. Although there is not yet evidence that CRISPR can be used to treat cancer, it’s not impossible. This advanced gene-editing technology has demonstrated that it could potentially be used to correct faulty, disease-causing genes in people, therefore curing their illness. Although this is a very complex area, research currently underway in China and USA may become a stepping stone for it future success.

References

[1] World Health Organisation Media Centre. Cancer fact sheet. http://www.who.int/mediacentre/factsheets/fs297/en/ (accessed 01 December 2017).
[2] Michael Le Page. Boom in human gene editing as 20 CRISPR trials gear up. https://www.newscientist.com/article/2133095-boom-in-human-gene-editing-as-20-crispr-trials-gear-up/ (accessed 28 November 2017).
[3] Michael Le Page. Gene editing starts to save lives as human trials get under way. https://www.newscientist.com/article/mg23231044-700-gene-editing-starts-to-save-lives-as-human-trials-get-underway/ (accessed 03 December 2017).
[4] Rozina Sabur. First gene-editing attempted in human body to cure disease. http://www.telegraph.co.uk/news/2017/11/16/first-gene-editing-attempted-human-body-cure-disease/ (accessed 28 November 2017).
[5] Dana Carrol, L. M. Wahl. Genome Engineering With Zinc-Finger Nucleases. Genetics 2011; 188(4): . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176093/ (accessed 03 December 2017).
[6] Heidi Ledford. CRISPR, the disruptor. https://www.nature.com/news/crispr-the-disruptor-1.17673 (accessed 28 November 2017).
[7] Bruce L. Levine, James Miskin, Keith Wonnacott, and Christopher Keir. Global Manufacturing of CAR T Cell Therapy. Molecular Therapy: Methods & Clinical Development 2017; 4(): 93.
[8] NCI staff. Researchers Use CRISPR Gene-Editing Tool to Help Turn Immune Cells against Tumors. https://www.cancer.gov/news-events/cancer-currents-blog/2017/crispr-immunotherapy (accessed 28 November 2017).
[9] Justine Alford. 9 burning questions about CRISPR genome editing answered. http://scienceblog.cancerresearchuk.org/2017/04/11/9-burning-questions-about-crispr-genome-editing-answered/ (accessed 30 November 2017).

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