Cutting Away Anaemia: Using CRISPR to Treat Sickle Cell Disease and Beta-Thalassaemia

lifescilens
Jan 8
4 min read

By Zihan Deng

▶︎ Twelve years ago, the discovery that CRISPR-Cas9, a bacterial defence system that cleaves invasive nucleotide sequences, could be modified to introduce specific breaks in target DNA rocked the scientific world¹. Today, the technology takes another step forward as it gains first approval as a treatment for two blood-related disorders.

Transfusion-dependent β-thalassaemia (TDT) and sickle cell anaemia (SCD) are both blood-related monogenic hereditary diseases. TDT is caused by a mutation in the human β-globin gene (HBB) that reduces or silences β-haemoglobin production, leading to precipitation of excess α subunits and death of red blood cells (RBC)². SCD occurs when a point mutation (E6V) in the HBB gene gives rise to sickle haemoglobin (HbS) which can aggregate into insoluble polymers that distort the cell, causing chronic pain and triggering vaso-occlusive episodes². Though many treatments have been trialed, there is no complete cure for either. Blood transfusion is the standard method, but to avoid iron overload, it is often coupled with chelation, which can introduce long-term complications such as hepatic and cardiac dysfunction. Though bone marrow transplant has the potential to be fully curative, matching donors are often difficult to find³. Therefore CRISPR, with its high specificity and ease of use, holds special promise as a targeted form of treatment.

Foetal haemoglobin (HbF) is a tetramer consisting of two α-globins and two γ-globins (α2γ2). It is the most abundant haemoglobin during gestation, but its production reduces with age, until HbA (α2β2) takes over as the most common form of adult haemoglobin⁴. The hypothesis that SCD and TDT could be cured through artificial reinitiating of HbF production was proposed decades ago, when it was first observed that elevated HbF levels in adults ameliorated SCD symptoms. However, the main switch controlling HbF synthesis was not discovered until 2008, when Orkins et al. revealed a stage-sensitive transcription factor, BCL11A, to be its repressor⁵. Building on these discoveries, the newly approved CRISPR drug, Casgevy, introduces a double-strand silencing knockout in the erythroid-specific enhancer region of the BCL11A gene (Figure 1).

To test the efficacy of Casgevy, Frangoul et al. performed a study on 2 patients, one with SCD (patient 1) and one with TDT (patient 2). Hematopoietic stem and progenitor cells (HSPC) were harvested from patients’ bone marrow, treated with CRISPR-Cas9, then intravenously re-infused. At 21 months after the treatment, neither patient required any more blood transfusions, and patient 1 experienced no more vaso-occlusive episodes. No off-target editing had occurred, and pancellular distribution of BCL11A-silenced RBCs had been observed. These clinical evidence demonstrates the efficiency and precision of Casgevy.

Despite the positive responses from patients, there are still questions that need to be answered. Firstly, the treatment was not without adverse events. Out of the 146 events recorded, five had been classified as serious. Though all had resolved with time and were expected to be connected to the preparations for marrow transplant rather than to the CRISPR treatment², a search for gentler methods, or perhaps improvements to the drug that would allow easier delivery, is required. Second, the small sample size makes it difficult to predict the effects of the treatment on the generalised scale, and though 19 more have joined the study, it is yet too early for results. Besides, the recentness of the study means that any potential long-term effects are yet to be seen. Third, though the study has proven CRISPR to be a possible curative strategy for SCD and TDT, the high expenses of the treatment (estimated to be around US $2 million per patient⁶) makes it difficult for the general public to access.

Still, successful treatment of SCD and TDT through CRISPR-Cas9 directed silencing of BCL11A is a landmark achievement, and the first approval of a CRISPR-based treatment could encourage other countries to follow suit, as well as promoting CRISPR’s application for other diseases, such as or in other fields, including regenerative medicine⁷ or even farming⁸. The search for improved drug delivery methods is also underway, and recently, another CRISPR-Cas9 drug aimed at in vivo delivery has entered phase one trial, with positive results, providing hope for easier, less painful treatment⁹. Though still a long way from becoming a standardised treatment, CRISPR’s future seems to shine bright. ◼️

Writer

Primary Editor

Peer-reviewers

Zihan Deng

Aanya Patel

Alex Chong & Alexa Lopez

References

Jinek, M. et al. A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science 337,816-821(2012)
Frangoul, H. et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. New England Journal of Medicine 384(3), 252-260 (2020)
Eckrich, M. J., Frangoul, H. Gene editing for sickle cell disease and transfusion dependent thalassemias - A cure within reach. Seminars in Hematology 60(1), 3-9 (2023)
Sankaran, V. G. et al. Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage - Specific Repressor BCL11A. Science 322, 1839-1842 (2008)
Mullard, A. CRISPR gets the glory in landmark approval, but haemoglobin research made it possible. Nature Reviews Drug Discovery 23, 14-15 (2024)
Sheridan, C. The world’s first CRISPR therapy is approved: who will receive it? Nature Biotechnology 42, 3-4 (2024)
Hsu, M. N. et al. CRISPR technologies for stem cell engineering and regenerative medicine. Biotechnol Adv. 37(8), 107447 (2019)
Ledford, H. CRISPR-edited crops break new ground in Africa. Nature 626, 245-246 (2024)
Longhurst, H. J. et al. CRISPR-Cas9 in vivo gene editing of KLKB1 for hereditary angioedema. N. Engl. J. Med. 390(5), 432–441 (2024)

Figure 1: Made by Zihan Deng using Biorender

Image: PublicDomainPictures. [DNA Illustration]. pixabay (2013). License