Rewriting DNA: A New Chapter in Sickle Cell Treatment?

Holly Dobbing, Fourth Year Medicine

In a 2021 issue of Science Translational Medicine, Lattanzi et al.¹ investigated the preclinical development of a protocol to correct the HBB gene in autologous (self-derived) stem cells, aiming to identify a potential functional cure for sickle cell disease.

Sickle cell disease is a genetic disorder caused by a point mutation in the HBB gene (responsible for encoding the 𝛽-globin subunit of haemoglobin²), affecting millions of people globally¹. This altered haemoglobin produces abnormal, crescent-shaped red blood cells (RBCs), known as sickle cells^1,2. These cells can cause severely painful vaso-occlusive crises, where the irregularly shaped RBCs lodge in small vessels, causing local hypoxia and tissue damage^1,2. 

Three treatments comprise the currently approved sickle cell disease therapy². Hydroxycarbamide has been shown to reduce vaso-occlusive crises by increasing patients’ proportions of healthy haemoglobin³, however it has been repeatedly reported to have various unpleasant side-effects; notably, rashes, sore skin, and ulcers². Additionally, red blood cell transfusions have been demonstrated to improve oxygen delivery to tissues but are therapeutically limited by iron overload and haemolytic and immunogenic transfusion reactions². Stem cell transplant with a matched donor offers a curative option for sickle cell disease^1,2, however it can be difficult to find a donor and there are significant risks for both donor and patient³. This treatment is referred to as allogeneic stem cell transplant. These limitations demonstrate a significant need for safer and more effective treatments in sickle cell disease. 

Gene editing is a novel approach allowing modification of the genome at specific loci to alter disease expression⁴. In their preclinical study, Lattanzi et al.¹ investigated the safety, efficacy, and clinical manufacturing feasibility of HBB gene-corrected stem cells in the treatment of sickle cell disease. The study proposed a direct correction of the HBB point mutation that is pathognomic of sickle cell disease¹, potentially treating the disease from within the DNA of the cells, rather than via lifelong medication and repeated procedures. 

The study initially performed gene correction on healthy control stem cells and illustrated effective HBB correction, but significant off-target effects¹. This prompted alteration of the protocol, and, with a modified approach, they generated cells with more corrected HBB alleles, and fewer off-target effects. Their findings matched the threshold for cure in the standard allogenic stem cell transplants. They then repeated the experiment using sickle cell disease patient-derived stem cells and illustrated analogous results. Lattanzi et al. concluded that the patient-derived corrected stem cells were capable of clinical scale long-term correction. This demonstrated the therapeutic potential of gene correction in sickle cell disease and supported the notion that a functional cure is possible. They also assessed the toxicological and tumorigenic potential of the process and found little evidence of adverse effects, abnormal cell development, or chromosomal changes¹. 

Unsurprisingly, the relative infancy of this approach naturally generates scepticism about the long-term success of the treatment. Other similar studies face comparable criticism^5-7. The consensus is that the early-stage evidence for safety and efficacy is adequate^5-7 but the limited execution in clinical settings means that more research is critical, and clinicians may need to be prepared for unanticipated toxicities³. 

Lattanzi et al. also failed to acknowledge the cost or accessibility issues associated with such specialist technology. Regardless of the clinical potential of gene correction approaches, the findings are somewhat deemed irrelevant if integration into clinical practice is blocked by cost, so despite the exciting findings, there remains an undeniable need to develop this into a more universally accessible treatment^3,7. 

That said, this study has provided the proof of concept and foundational support for future clinical trials investigating the use of gene correction in sickle cell disease treatment. Similar studies have since corroborated the durability and efficacy of gene editing in sickle cell disease^5,6. Everette et al.⁵ used a similar strategy to illustrate correction of the sickle cell disease HBB-allele with high efficacy and minimal off-target effects. Xu et al.⁶ undertook further analysis to identify the optimal protocol and ensure patient safety. Cumulatively, this has encouraged recent approval in the UK for the use of gene correction in the treatment of severe sickle cell disease⁷ (link to BBC article – https://bbc.co.uk/news/health-67435266)). Hopefully, these promising advancements in gene correction therapy mark the beginning of a better experience for patients with sickle cell disease. 

References

(1) Lattanzi A, Camarena J, Lahiri P, Segal H, Srifa W, Vakulskas CA, et al. Development of B-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. American Association for the Advancement of Science (AAAS); 2021.

(2) Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nature reviews. Disease primers. 2018; 4 (1): 18010. 10.1038/nrdp.2018.10.

(3) Crossley M, Christakopoulos GE, Weiss MJ. Effective therapies for sickle cell disease: are we there yet? Trends in genetics. 2022; 38 (12): 1284-1298.
10.1016/j.tig.2022.07.003

(4) Alayoubi AM, Khawaji ZY, Mohammed MA, Mercier FE. CRISPR-Cas9 system: a novel and promising era of genotherapy for beta-hemoglobinopathies, hematological malignancy, and hemophilia. Annals of hematology. 2023; 1
10.1007/s00277-023-05457-2.

(5) Everette KA, Newby GA, Levine RM, Mayberry K, Jang Y, Mayuranathan T, et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Springer Science and Business Media LLC; 2023.

(6) Xu L, Lahiri P, Skowronski J, Bhatia N, Lattanzi A, Porteus MH. Molecular dynamics of genome editing with CRISPR-Cas9 and rAAV6 virus in human HSPCs to treat sickle cell disease. Molecular therapy. Methods & clinical development. 2023; 30 317-331. 10.1016/j.omtm.2023.07.009.

(7) Walsh F. Casgevy: UK approves gene-editing drug for sickle cell. BBC News. 2023 Nov 16; [accessed 17 November 2023]; Available from:
https://www.bbc.co.uk/news/health-67435266