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CRISPR

CRISPR: the Future of Cancer Research

Paige Chandran Blair—McMaster University Biochemistry 2023

Introduction

Cancer has become one of the leading global public health issues, exemplified by its status as the second leading cause of death worldwide in 2015 (1). The magnitude of cancer’s impact is predicted to surge over the next two decades, with the instance rate expected to increase by 70%. Despite humanity’s long awareness of cancer, treatment design has proved to be incredibly difficult as cancer involves complex physiological alterations, several mutations, translocations and chromosomal insertions/deletions. Cancer involves changes in genetic material that either turn genes off (such as tumour suppressors), or turn genes on (such as oncogenes). This ultimately leads to unregulated cellular growth (2). Consequently, gene editing is rising to the forefront of developing treatments for cancer,with the CRISPR-Cas system leading the way. 

CRISPR Technologies

The CRISPR-Cas technique is based on a prokaryotic immune defence mechanism (1). Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) systems involve guide RNAs (gRNA) and an endonuclease known as the CRISPR-associated (Cas) protein (3). Guide RNAs are designed by researchers to identify and guide the Cas DNA cutting enzyme to the target DNA where Cas cuts the DNA to creates a double-stranded break, illustrated in the figure below.

How CRISPR Is Changing Cancer Research and Treatment - National Cancer  Institute
Figure 1: Mechanism of CRISPR-Cas9 technology showcasing the recognition of a target sequence, its cleavage, and the insertion of new genetic material. 
SOURCE: National Cancer Institute (2020)

Once the target gene is cut, the DNA can either be altered to inactivate the gene and create ‘knockouts’ or new segments can be added to create novel cellular functions. Researchers have taken advantage of this system because it presents the opportunity to accurately and easily make modifications at the genetic level such as adding and removing specific nucleotides without requiring separate cleaving enzymes (4). 

Current CRISPR-Based Cancer Treatments: 

CRISPR is a valuable asset to cancer treatments because cancer consists of several mutations making it difficult to target. Due to CRISPR’s versatility, accuracy, and precision, it is widely applicable to many branches of cancer research. CRISPR is currently driving research in cancer screening technologies, and providing drastic improvement on immunotherapies such as Chimeric Antigen Receptor (CAR) T-cell therapy (5). CRISPR-based applications to cancer screening are currently being conducted to identify genes related to drug resistance/sensitivity, genes pertaining to cellular vulnerability to environmental toxins, and genes with a role in the development of diseases. CAR T-cell therapy is a leading immunotherapy in which a patient’s T cells are removed, altered to express the chimeric antigen receptor (CAR) so they are better able to bind and kill cancer cells, then grown in large quantities, and reinserted into the patient as illustrated in the figure below (6).

PDF] Neurological updates: neurological complications of CAR-T therapy |  Semantic Scholar
Figure 2: General process of CAR T-Cell Therapy from synthesis of CAR T-cells to insertion back into patient. 
SOURCE: National Cancer Institute (n.d.)

CAR T-cell therapy has been previously limited due to a lack of proliferation and persistence of CAR T-cells in toxic tumour microenvironments common to patients with advanced stages of cancer (7). However, novel CRISPR-edited CAR T-cells have demonstrated increased potency against tumours. The CRISPR system is applied to enhance T-cell function by ‘knocking out’ a protein that limits CAR T-cell activation (8). 

The Future of CRISPR Research: 

CRISPR based technologies currently have several limitations which future studies must overcome. First, future technologies must improve the delivery of CRISPR treatments to cancerous cells (3). Currently, two major methods are being developed to address this delivery problem; viruses and nanocapsules. Viruses are exploited to deliver CRISPR components to a specific organ (e.g. liver) using a virus which naturally targets that organ, while nanocapsules are designed to bring CRISPR components directly to target cells. Human cancer research is solely ex vivo, meaning that cells are removed and edited outside of the body as described with CAR T-cell therapy. However, future treatments may move beyond this and begin in vivo treatment design. Finally, while treatments such as CAR T-cell therapy have had several positive results in treating hematologic malignancies (i.e. blood cancers) efficacy has yet to be demonstrated in treating solid tumours (7).With CRISPR based technologies rising to the forefront of personalized cancer treatments, new hope is growing in research to address cancer’s future health threat.

References

(1) Ratan ZA, Son Y-J, Haidere MF, Uddin BMM, Yusuf MA, Zaman S Bin, et al. CRISPR-Cas9: a promising genetic engineering approach in cancer research. Ther Adv Med Oncol [Internet]. 2018 Jan 1 [cited 2021 Feb 19];10:1758834018755089. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29434679 

(2) CRISPR Cancer Research [Internet]. Synthego. 2021 [cited 2021Feb19]. Available from: (3) NCI Staff. How CRISPR Is Changing Cancer Research and Treatment [Internet]. National Cancer Institute. 2021 [cited 2021Feb19]. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treatment 

(4) Questions and Answers about CRISPR [Internet]. Broad Institute. 2018 [cited 2021Feb20]. Available from: https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr

(5) Spencer NY. Overview: What is CRISPR Screening [Internet]. Integrated DNA Technologies. Integrated DNA Technologies; 2019 [cited 2021 Feb 19]. Available from: https://www.idtdna.com/pages/education/decoded/article/overview-what-is-crispr-screening

(6) NCI Staff. CAR T-Cell Therapy [Internet]. National Cancer Institute. [cited 2021 Feb 19]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy

(7) Salas-Mckee J, Kong W, Gladney WL, Jadlowsky JK, Plesa G, Davis MM, et al. CRISPR/Cas9-based genome editing in the era of CAR T cell immunotherapy. Hum Vaccin Immunother [Internet]. 2019 May 4 [cited 2021 Feb 19];15(5):1126–32. Available from: https://www.tandfonline.com/doi/full/10.1080/21645515.2019.1571893

(8) University of Pennsylvania School of Medicine. CRISPR-edited CAR T cells enhance fight against blood cancers [Internet]. ScienceDaily. ScienceDaily; 2020 [cited 2021Feb19]. Available from: https://www.sciencedaily.com/releases/2020/12/201207161535.htm

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