Base editing is a new gene editing technology that is able to create gene knockouts, correct errors in genetic code, or fix mutations in the DNA of living cells. The first base editors were established in 2016 by a team led by David Liu at Harvard University and another led by Akihiko Kondo at Kobe University. Since then, a lot of excitement has surrounded the developments of the novel technology that has made headlines for scientific feats such as curing "incurable" leukemia.
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Base editing vs. CRISPR and other genome editing tools
In the ten years since the advent of CRISPR-Cas9 technology, gene editing has become easier, faster, and more accessible. However, while CRISPR is a revolutionary technology, it is not without its limitations, just like earlier genome editing tools, particularly in the case of making small, nucleotide base-sized modifications to the genome.
More recently, base editing technology has emerged on the scene. In contrast to previous gene editing technologies, base editing easily makes single base pair changes in the genome. This function of base editing bestows it a wealth of clinical utilities.
This exciting new approach to gene editing has the potential to be leveraged to create gene knockouts, correct errors in DNA, and repair mutations within living cells.
Genetic mutations play a significant role in the initiation and progression of disease. Studies have shown that most disease-causing pathogenic mutations are single nucleotide polymorphisms that are small enough to be challenging for gene editing techniques such as CRISPR but not base editing. Before this novel technology emerged, complex processes of using a template of exogenous DNA to replace the mutations along with the introduction of DNA double-strand breaks. While this was possible and could be conducted with CRISPR and other gene editing technologies, their success rate has been low in cells isolated from patients.
Theoretically, cell-based therapeutics have the potential to develop new and effective treatments for patients with solid tumors. However, with CRISPR or other previous gene editing technologies, this would require the introduction of double-strand breaks to carry out the multiple gene-editing events that would be necessary, which is undesirable.
Simultaneous multiple double-strand breaks that occur with CRISPR technology are risky because it opens up the possibility that the cell's innate DNA repair processes may fail and introduce further mistakes that could result in the initiation of cancer or cellular transformation.
Base editing, not the other hand, overcomes this key limitation as it does not introduce these risky double-strand breaks when modifying a base pair. Therefore, it limits the chance of large alterations to the genome. Because of this advantage, base editing has an attractive safety profile regarding its choice as a tool for cell therapy.
Where are base editing technologies being developed?
Base editing has been developed by scientists working within several different academic groups. As mentioned above, the method was first established by a team led by David Liu at Harvard University and another led by Akihiko Kondo at Kobe University. Teams have described base editing with the same principles at other institutions. This version has formed the basis of the cell-based therapeutics that Beam Therapeutics is currently developing in Boston, US.
Systems that differ from the David Liu method is the Horizon Discovery system under development at Rutgers University, which builds on the work of Shengkan Jin's laboratory. It is likely that both systems will be used in the same applications as there is an overlap in functionality and both systems are capable of accurately knocking out gene expression.
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Achievements of base editing technology
At the end of 2022, it was reported that a teenager in the UK was cured of her incurable leukemia after being the world's first person to be treated with base editing therapy.
The 13-year-old had been suffering from T-cell acute lymphoblastic leukemia, an incurable form of cancer marked by an inability of the patient's T cells to mature effectively. While previous years have seen a number of breakthroughs with gene therapies for cancer, T-cell acute lymphoblastic leukemia presented a particular challenge for this technology. This is because editing T cells to target other T cells often causes the modified T cells to seek and destroy other modified T cells.
With base editing technology, scientists were able to add several new modifications to the T cells that altered key markers that identify the immune cells as T cells. As a result, the edited cells were invisible to other T cells.
The scientists also removed all markers that were unique to the donor, meaning that the cells can now be used universally. Importantly, this means that an off-the-shelf drug could be developed from the work done to cure this teenage patient of her cancer with base editing.
We can expect many more breakthroughs like this as base editing matures. Hopefully, more treatments and even some cures will be developed with the help of this cutting-edge technology.
- Anjali A Sarkar. 2021. CRISPR 2.0: Base Editing in the Groove [online]. Genetic Engineering & Biotechnology News. Available at: www.genengnews.com/.../ (Last accessed December 2022)
- Larissa Warneck-Silvestrin. 2021. Base Editing: The Next Frontier in Genome Editing Technology [online]. Labiotech. Available at: https://www.labiotech.eu/interview/base-editing-horizon-discovery/ (Last accessed December 2022)
- Rich Haridy. 2022. Teenager's "incurable" leukemia cured by new base editing gene therapy [online]. News Atlas. Available at: newatlas.com/.../ (Last accessed December 2022)