Successful Use of Gene Therapy In Fighting Leukaemia

 by Zirui Zhou

Alyssa, a 13-year-old girl from the UK, was diagnosed with T-cell acute lymphoblastic leukaemia (T-ALL) in May 2021 [1]. In T-ALL, at least 20 percent of immature T-cells fail to mature properly and continue to grow and divide uncontrollably. These immature T-cells become cancerous and interfere with the production of normal white blood cells by crowding out healthy blood cells, which may weaken the patient’s immune system. [2]

All other treatments for Alyssa’s leukaemia had failed, including Chemotherapy and a bone-marrow transplant. At that time, the disease which Alyssa had seemed to be incurable and the only next step would have been palliative care.

However, Alyssa decided to do the base-edited T-cells therapy in the first ever use of such cell therapy at Great Ormond Street Hospital for Children, holding the idea that it would help others know what they need to do after taking the experimental new treatment for the disease. [3]

What happened next was that the large team of doctors and scientists at Great Ormond Street Hospital for Children engineered a new type of T-cell that was able to hunt down and kill Alyssa's cancerous T-cells. They started with healthy T-cells that were extracted from a donor and modified them. The team made three modifications to the gene of the T-cells: the first base edit disabled the T-cells targeting mechanism so they would not assault Alyssa's body, the second removed a chemical marking called CD7, which is on all T-cells, and the third edit was to prevent the cells from being killed by a chemotherapy drug. This third step instructed the modified T-cells to attack everything with CD7, so removing CD7 in the second step was essential for these T-cells to prevent them from killing themselves, and keep them only hunting for the cancerous T-cells in the body. To put it simply, the T-cells from a donor were edited to allow them to destroy the cancerous T-cells while not attacking Alyssa’s own immune system, and then the modified cells were infused into Alyssa.

The team turned to base editing to engineer the T-cells. Base editing was discovered six years ago in a Harvard University laboratory. It allows scientists to zoom into a precise part of the genetic code and then alter the molecular structure of just one base, converting it into another base and therefore changing the genetic instructions. However, despite the fact that CRISPR-Cas9 is the Nobel Prize-winning gene-editing technology, they did not use this technology to edit the gene of the T-cells. This is because CRISPR-Cas9 works by cutting a disease-causing gene out of the DNA double helix before sticking it back up. Instead of making a full cut, the base editing technique nicks a single strand of DNA, while changing a base of DNA on the other strand at the same time. (Figure 1) Following that, the cell then repairs that nick using the just-edited DNA as its template. Researchers often compare base editing to using a pencil and an eraser, while the traditional CRISPR system is more like using scissors and glue. [4] As CRISPR-Cas9 gene editing introduces double-strand breaks while base editing avoids them, the errors of gene editing can be minimised with base editing. [5]

*Figure 1: Conventional CRISPR-Cas9 gene editing (left panel) introduces double-strand breaks, which can lead to off-target effects. Base editing (right panel) avoids double-strand breaks, thereby minimising errors. [5]

Alyssa was left vulnerable to infection after instructing with the modified T-cells, as the designer cells attacked both the cancerous T-cells in her body and those that protect her from disease. After a month of gene therapy, Alyssa was given a second bone-marrow transplant to regrow her immune system.

After six months, the cancer was undetectable. Alyssa was “leukaemia free” after the world-first use of cell engineering therapy. Dr Liu, one of the inventors of base editing at the Broad Institute, said the "therapeutic applications of base editing are just beginning". Recent successes in genetic medicine have paved the path for a broader second wave of therapies and laid the foundation for next-generation technologies. [6]

 

 References:

[1] Gallagher, J. (2022) Base editing: Revolutionary therapy clears girl’s incurable cancer, BBC News. Available at: https://www.bbc.co.uk/news/health-63859184 (Accessed: 05 July 2023).

[2] Person (2021) Your guide to T-cell acute lymphoblastic leukemia, Healthline. Available at: https://www.healthline.com/health/leukemia/t-cell-acute-lymphoblastic-leukemia (Accessed: 05 July 2023).

[3] Girl, 13, ‘leukaemia-free’ after world-first use of cell engineering therapy (2022) The Independent. Available at: https://www.independent.co.uk/news/science/scientists-medical-research-council-tcell-leicester-medics-b2242976.html (Accessed: 05 July 2023).

[4] Dunn, A. (no date) How a gene-editing breakthrough from a Harvard Lab saved the life of a girl with leukemia, Business Insider. Available at: https://www.businessinsider.com/what-is-base-editing-gene-editing-leukemia-breakthrough-2022-12?r=US&IR=T (Accessed: 05 July 2023).

[5] Anjali A. Sarkar, P. (2023) CRISPR 2.0: Base editing in the groove, GEN. Available at: https://www.genengnews.com/topics/genome-editing/crispr-2-0-base-editing-in-the-groove/ (Accessed: 05 July 2023).

[6] Bulaklak, K. and Gersbach, C.A. (2020) The once and future gene therapy, Nature News. Available at: https://www.nature.com/articles/s41467-020-19505-2 (Accessed: 05 July 2023).