A recently published article presented a new form of treatment for sickle cell disease in mice. Researchers from the Broad Institute, St. Jude Children’s Research Hospital used a new form of a gene-editing technique called base editing to edit a specific base pair that is considered to be the underlying genetic pathology in sickle cell disease.
Sickle Cell Anemia Courtesy of Bruce Blaus
Genetic mutation in sickle cell disease
Sickle cell disease is a genetic condition that follows an autosomal recessive pattern. Males and females are equally affected, and both parents need to carry the gene for the disease to manifest in the offspring. In this disease, a genetic mutation occurs in the form of a single nucleotide change. A substitution of thymine for adenine occurs at the sixth codon level, and this results in an amino acid change. The sixth position of the beta chain of hemoglobin contains valine instead of glutamate. This amino acid change results in structural and functional changes in the hemoglobin, the oxygen-carrying protein in the blood. Eventually, the oxygen-carrying capacity of blood is reduced, and upon exertion, the patient feels severe pain, which can result in life-threatening complications like stroke or heart attack.
Previous approach
Previously, the gene-editing technology called CRISPR focused on editing the double-helical structure of DNA. This involved making copies of the DNA and shutting off the target gene. In this approach, there was a risk of damaging the DNA strands. This approach was being researched by companies like Editas Medicine, based in Massachusetts, and CRISPR Therapeutics, based in Switzerland. A patient was treated using this approach in 2019.
Current technique
The current approach, sometimes referred to as CRISPR 2.0, focuses on editing only a base pair in the DNA. Using this approach, an A-T pair of nucleic acids can be edited and changed into G-C pairs of nucleic acids. Optimum and required integration of these edits and conversions will eventually lead to a transformation of red blood cells in the patient suffering from sickle cell disease, and it will eventually lead to the elimination of the disease. This approach is termed a definitive improvement on the previous gene-editing technology called CRISPR, as it is less invasive, more precise, and does not involve any damage to the strands of DNA.
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According to a co-author of this article, David Liu, the current research complements the findings of a previous work by Beam Therapeutics, a biotech company exploring similar methods of treatment for this disease. This company was co-founded by David Liu.
Future direction
The focus of current research has only been on exploring the treatment options for this disease in mice. Having shown the potential of this base editing method in mice and having two distinct validations of this approach, the researchers would be looking to get the requisite approvals and attempt to treat sickle cell disease in humans in the future. They plan on doing this by initiating clinical trials to test this technique in humans. Researchers hope that this approach can be enhanced further to develop a single-administration treatment for patients with sickle cell disease and, hopefully, find a definitive cure for this disease in humans.
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References
Newby, G.A., Yen, J.S., Woodard, K.J. et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature 595, 295–302 (2021). https://doi.org/10.1038/s41586-021-03609-w
