Joshua A. Bougadis, Upper Canada College, Toronto, Ontario, Canada
Summary:
Sickle Cell Disease is a group of hereditary red blood cell disorders that has become a focal point of genomic research. This potentially fatal disease, affecting millions worldwide, has previously been treated with inadequate palliative care options. However, numerous studies have revealed that genome editing using CRISPR Cas-9 offers the possibility of not only alleviating the symptoms of Sickle Cell Disease, but also curing the disease and removing its hereditary nature. Through continued research, trials, and usage, CRISPR Cas-9 treatment could also be applied to genome editing for a plethora of similar blood-borne genetic diseases. Despite this, the immense cost of this procedure and the social barriers that prevent individuals from acquiring this treatment warrants further research. Still, this treatment offers an opportunity to treat and cure a number of genetic diseases, improving the health of many worldwide.
Review Article:
Sickle Cell Disease (SCD) is the most common hemoglobinopathy, with 300,000 children born with homozygous SCD worldwide, anually (Wastnedge et al., 2018). SCD is a group of hereditary blood disorders, including sickle cell anemia and Tay-Sachs disease, amongst many others (Johns Hopkins Medicine, 2022). This disease has come to the forefront of genome editing research using CRISPR Cas-9 (clustered regularly interspaced short palindromic repeats - associated protein 9) due to the possibility of CRISPR treatment alleviating all symptoms and the hereditary nature of the disease (Frangoul et al., 2021).
Figure 1: Normal red blood cells vs. sickle cells in our bloodstream (Horsager-Boehrer, R., 2019).
SCD is a single nucleotide polymorphism of the sixth amino acid in the hemoglobin beta-chain, creating abnormal hemoglobin and red blood cells (Pauling, 1949). Red blood cells with normal hemoglobin are disk-shaped and freely move throughout the body to transport oxygen to tissues. However, SCD renders red blood cells sickle-shaped, rigid, and sticky, causing them to block blood vessels and restrict the transport of oxygen-carrying blood (Mayo Clinic, 2022). Sickled cells also only live for 10 to 20 days compared to the normal 120 days. Therefore, when the spleen attempts to filter blood, sickled cells block the spleen and damage it, fostering greater risks of infection (Cedars-Sinai, 2021).
According to the National Health Service (2017), SCD requires lifelong treatment, such as:
Hydroxycarbamide: inhibits cell synthesis and promotes fetal hemoglobin production (Nevitt et al., 2017).
Crizanlizumab: a monoclonal antibody medication that mitigates vaso-occlusive crises (Kenneth et al., 2017).
Antibiotics: protects against infection.
Dietary supplements such as folic acid for fetal hemoglobin production.
Blood transfusions for low red blood cell counts.
Allogenic bone marrow transplants: uses “chemotherapy for conditioning to remove the recipient's cells and replacing them with the donor cells free of sickling” (Ashrobi et al., 2021).
While these treatments may alleviate or lessen the symptoms of SCD, seldom are they curative. Bone marrow transplants offer a cure for SCD, but they are performed infrequently as the procedure has many risks and limitations. For instance, bone marrow transplants require a bone marrow match and treatment before the age of 16 (MyHealth Alberta, 2021; Nationwide Children’s, 2018). It also often leads to graft-versus-host disease (Cleveland Clinic, 2020). Genome editing, however, provides a treatment for SCD that can cure the disease and remove the heritability of SCD with minimal risk (World Health Organization, 2006).
According to Medline Plus (2022), genome editing is a set of technologies that allows scientists to remove, add, or replace DNA from an organism’s genome. In 2009, a new genome-editing tool, CRISPR Cas-9, was invented, offering a simpler, cheaper, and more accurate way to carry out genetic modification.
The process of genome editing with CRISPR Cas-9 has been applied to bloodborne genetic disorders such as SCD, leukocytosis, and hemophilia (Mayo Clinic, 2021; MedLine Plus Genetics, 2022). It involves a patient's hematopoietic stem cells being removed and modified with CRISPR ex vivo (Kaiser. J., 2021). Chemotherapy then eliminates the disease-causing blood cells from the patient’s body so that the fetal hemoglobin, modified ex vivo, may replace the mutated cells (Henderson, H., 2022).
Ex vivo gene editing is a potential game-changer in terms of prognosis, family planning, and patient quality of life. These treatments could mitigate health costs associated with treating sickle cell-related health problems, especially in some countries in the Global South with poor healthcare infrastructures.
There are currently two viable treatments for SCD using CRISPR Cas-9. In one treatment, the BCL11A gene, which regulates the synthesis of mutated hemoglobin is removed via the removal of the BCL11A transcription factor. Hence, the expression of healthy hemoglobin is promoted (Frangoul, H., 2021; Synthego, 2022).
The other treatment for SCD involves base mutation and introduces “a donor template containing the normal sequence of the gene” so that the “mutation is corrected when the cell repairs the DNA break with the template”.
Figure 2: Genome editing treatment of SCD via direct modification of the single-base mutation (Sickle Cell Gene Therapy Using CRISPR, 2022).
Both ex vivo genome editing processes with CRISPR Cas-9 have higher efficacy and lower risk compared to current treatments. Seven successful trials have been completed on patients with SCD that permanently cured the disease, removed its heritability, and eliminated all pain crises. (Henderson, H., 2022). Additionally, within all genome editing trials, there was no evidence of off-target editing, adverse effects, or severe immune reactions beyond the effects of chemotherapy (Frangoul, H., 2021).
However, the scalability and cost of CRISPR Cas-9 may limit its globalization and widespread administration. The cost to administer the treatment is between $1-2 million and is hence not a feasible option for the majority of individuals possessing SCD (Henderson, H., 2022).
While further research needs to be performed to advance this experimental medical innovation, the use of genome editing with CRISPR Cas-9 has the potential to become an effective alternative treatment for SCD and other bloodborne genetic disorders. This treatment must become affordable, viable, and widespread to provide a solution to this global disease. In the coming years, scientists will continue research of genome editing using CRISPR Cas-9 technology in order to better the lives of SCD patients worldwide and potentially provide equity for future generations.
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