5 January 2026

Gene therapy in inherited blood disorders: A spotlight on sickle cell disease and beta‑thalassaemia

 

Inherited blood disorders are a group of conditions that alter the production, structure or function of blood cells, often requiring coordinated long-term management of patients. Haemoglobinopathies represent a subgroup of inherited blood disorders characterised by genetic changes in the haemoglobin, a key protein in the blood responsible for oxygen transport. Sickle cell disease (SCD) and beta-thalassaemia are two examples of haemoglobinopathies [1].

Globally, millions of patients are affected by beta-thalassaemia showing regional clusters across Africa, the Middle East, the Indian subcontinent, Southeast Asia and the Mediterranean, whereas SCD is most concentrated in sub-Saharan Africa, where 80% of global cases occur [2,3]. According to the National Haemoglobinopathy Registry, in 2022, there were approximately 14,940 patients with SCD and 1,545 patients with beta-thalassaemia in the UK [4]. This means that despite being common inherited disorders in certain minority ethnic groups, these are still classified as rare diseases within the UK [5].

Sickle cell disease

SCD, also referred to as sickle cell anaemia, is an autosomal recessive, inherited blood disorder. It is caused by a mutation in the HBB gene that encodes a subunit of the haemoglobin protein called beta-globin (see Figure 1). This mutation results in abnormal haemoglobin, which then causes red blood cells to become sickle-shaped (Figure 1). Patients with SCD report acute pain episodes, referred to as a ‘sickle cell crisis’ or ‘vaso-occlusive crisis’ [6].

Figure 1. Sickle cell disease causes red blood cells to be sickled in shape, which leads to vascular occlusions.

SCD is often referred to as a ‘neglected disease’. Recent data from a comparative report commissioned by the National Health Service (NHS) Race and Health Observatory showed that only 30% of adults with SCD felt that they received pain relief in a timely manner, whereas 20% of babies with SCD were not provided with the recommended standard treatment in the UK [7]. Furthermore, hospital admissions for SCD have increased by over 50% in the past decade and are associated with an increase in mortality. These statistics suggest ongoing challenges in acute and long-term care pathways [7].

It is important to mention that racial bias has been identified as a significant factor contributing to the suboptimal care of patients with SCD. Many patients are often disbelieved, stereotyped and face disparities in accessing timely treatment and overall quality of care [8].

Beta-thalassaemia

Beta-thalassaemia is an inherited autosomal recessive haemoglobinopathy also caused by mutations in the HBB gene. In this case, the changes to the gene lead to reduced or absent beta-globin production, resulting in an imbalance between alpha- and beta-globin chains that make up the haemoglobin [9,10]. This then causes an imbalance between the production and destruction of red blood cells. The increased destruction rate leads to chronic anaemia and its associated complications [11].

The management of beta-thalassaemia relies heavily on lifelong blood transfusions, which frequently lead to an excess of iron in the bloodstream and consequently, organ damage [11]. Iron chelation is a therapy that aims to remove excess iron and mitigate its risks; however, adherence rates are often poor owing to the demanding schedules and gastrointestinal side effects [12].

Curative bone marrow transplantation is available to those with a compatible donor [12]. This approach carries substantial risks though, leaving many patients without a viable long-term solution. Such limited access to effective management options underscores a major unmet need for therapies that provide relief without the significant burden associated with current treatment options.

“I don’t have a donor for the bone marrow transplant so until gene therapy is offered, there is no cure for me … I just want to be free and cured” – Standards of clinical care of children and adults living with thalassaemia in the UK, 2023

What are gene therapies and why do they matter?

Diseases such as inherited blood disorders were once managed through lifelong supportive care. However, innovative genetic approaches are now bringing new hope for patients, with gene therapy standing out as a promising therapeutic approach [1].

Gene therapies target the underlying genetic causes of the disease, having the potential to cure inherited disorders, such as haemoglobinopathies [13]. Their mechanism of action is to alter or replace faulty genes, using approaches such as gene replacement, gene suppression or gene-editing (see Figure 2).

Recent gene therapy breakthroughs

Recent breakthroughs in gene therapies are proving promising to improve the lives of those living with SCD and beta-thalassaemia. In 2023, Vertex’s exagamglogene autotemcel (exa-cel) was approved by the Medicines and Healthcare products Regulatory Agency in the UK for the treatment of SCD and transfusion-dependant beta-thalassaemia and as of 31 January 2025, is approved for use on the NHS in England [14,15]. This is the first clustered regularly interspaced short palindromic repeats (CRISPR)–based gene-editing therapy and is a one-time therapy that edits the BCL11A gene in the patient’s own stem cells. The edited cells are reinfused, enabling the production of healthy red blood cells and foetal haemoglobin, thus preventing disease manifestations (Figure 2) [16].

Figure 2. The multistep process of exa-cel treatment in patients with sickle cell disease

In clinical trials, 97% patients with SCD treated with exa-cel were free of ‘crises’ for a 12-month period or more, and 91% of patients with transfusion-dependant beta-thalassaemia no longer required red blood cell transfusions for at least 12 months after treatment, with no safety concerns reported [16,17]. The Chief Executive of the Sickle Cell Society, John James OBE, celebrated this historic milestone and labelled it as “a turning point in the fight against sickle cell” [18]; meanwhile, the Executive Director of the UK Thalassaemia Society, Romaine Maharaj, believes that “we stand on the brink of a revolutionary breakthrough” for patients [19].

Besides exa-cel, several other gene therapies have gained international regulatory approval. Bluebird Bio’s lovotibeglogene autotemcel was approved in 2023 by the Food and Drug Administration in the USA for SCD. This gene therapy works by introducing a functional beta-globin gene to the patient’s own stem cells to enable the production of anti-sickling haemoglobin [20]. Bluebird Bio’s betibeglogene autotemcel, which has a similar mechanism of action, received conditional approval from the European Medicines Agency in 2019 for transfusion-dependant beta-thalassaemia [21]. However, neither therapy is currently available on the NHS.

Current limitations

The major limitation of these innovative approaches is the high cost, with gene therapies averaging at approximately £1.7 million per treatment [22]. Financial, regulatory and logistical barriers limit access of both patients and healthcare systems to gene therapies and must be overcome to ensure patients receive the needed treatment. Although gene therapies offer significant promise, there are safety considerations, such as unintended genetic changes, which require careful monitoring and ongoing research to mitigate these outcomes [23].

Conclusions

Tim Chronis, the first patient in the UK to receive exa-cel, has beta-thalassaemia and described the outcomes of his treatment as “remarkable”, noting that his blood counts began to rise “on their own for the first time ever” [24]. Another patient described exa-cel as a therapy that could finally “bring an end to the perpetual challenges that people like me live with” [25], highlighting the potential of gene therapies.

The recent advances in gene therapies for haemoglobinopathies mark a turning point in medicine, bringing us closer than ever to the possibility of long-lasting cures and better outcomes for patients facing the burden of intensive regimens and recurrent disease complications. These breakthroughs also pave the way for gene-editing approaches in other areas, offering hope for the future treatment of rare diseases and the promise to alleviate the devastating impact on patients in the UK and worldwide.

 

References

  1. UK Government. Guidance: Understanding haemoglobinopathies. Available at: https://www.gov.uk/government/publications/handbook-for-sickle-cell-and-thalassaemia-screening/understanding-haemoglobinopathies. Accessed December 2025.
  2. Soteriades ES, Angastiniotis M, Economidou EC, et al. The disease burden of β-thalassaemia revisited. Hematology 2025; 30 (1): 2551450.
  3. World Health Organization. Sickle-cell disease. Available at: https://www.who.int/news-room/fact-sheets/detail/sickle-cell-disease. Accessed December 2025.
  4. National Haemoglobinopathy Registry. Annual Report 2021/2022. Available at: https://nhr.mdsas.com/wp-content/uploads/2024/03/NHR-Annual-Report-2021-2022.pdf. Accessed December 2025.
  5. UK Government. England Rare Diseases Action Plan 2025: Main report. Available at: https://www.gov.uk/government/publications/england-rare-diseases-action-plan-2025/england-rare-diseases-action-plan-2025-main-report. Accessed December 2025.
  6. National Heart, Lung, and Blood Institute. What is sickle cell disease? Available at: https://www.nhlbi.nih.gov/health/sickle-cell-disease. Accessed December 2025.
  7. NHS Race and Health Observatory. Sickle cell comparative review to inform policy report. Available at: https://nhsrho.org/wp-content/uploads/2025/06/SICKLE-CELL-COMPARATIVE-REPORT-.pdf. Accessed December 2025.
  8. Sickle Cell Society. No one’s listening. Available at: https://www.sicklecellsociety.org/wp-content/uploads/2021/11/No-Ones-Listening-Final.pdf. Accessed December 2025.
  9. Musallam KM, Lombard L, Kistler KD, et al. Epidemiology of clinically significant forms of alpha- and beta-thalassemia: A global map of evidence and gaps. Am J Hematol 2023; 98 (9): 1436–1451.
  10. Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta thalassemia. Available at: https://www.ncbi.nlm.nih.gov/books/NBK531481/. Accessed December 2025.
  11. Sadiq IZ, Abubakar FS, Usman HS, et al. Thalassemia: Pathophysiology, diagnosis, and advances in treatment. Thalass Rep 2024; 14 (4): 81–102.
  12. UK Thalassaemia Society. Standards for the clinical care of children and adults living with thalassaemia in the UK, 4th edition, 2023. Available at: https://ukts.org/wp-content/uploads/2021/02/Standards-for-the-Clinical-Care-of-Children-and-Adults-Living-with-Thalassaemia-in-the-UK-4th-Edition-2023.pdf. Accessed December 2025.
  13. Qie B, Tuo J, Chen F, et al. Gene therapy for genetic diseases: Challenges and future directions. MedComm (2020) 2025; 6 (2): e70091.
  14. UK Government. MHRA authorises world-first gene therapy for sickle cell disease and transfusion-dependent thalassemia. Available at: https://www.gov.uk/government/news/mhra-authorises-world-first-gene-therapy-that-aims-to-cure-sickle-cell-disease-and-transfusion-dependent-thalassemia. Accessed December 2025.
  15. NHS England. Revolutionary gene-editing therapy for sickle cell ‘offers hope for a cure’ for NHS patients. Available at: https://www.england.nhs.uk/2025/01/revolutionary-gene-editing-therapy-for-sickle-cell/. Accessed December 2025.
  16. Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med 2024; 390 (18): 1649–1662.
  17. Locatelli F, Lang P, Wall D, et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. N Engl J Med 2024; 390 (18): 1663–1676.
  18. Sickle Cell Society. Gene therapy approved for sickle cell disorder. Available at: https://www.sicklecellsociety.org/gene-therapy-approved-for-sickle-cell-disorder/. Accessed December 2025.
  19. British Society for Haematology. England approves beta-thalassaemia gene therapy. Available at: https://b-s-h.org.uk/about-us/news/england-approves-beta-thalassaemia-gene-therapy. Accessed December 2025.
  20. Bluebird Bio. bluebird bio announces FDA approval of LYFGENIA™ (lovotibeglogene autotemcel) for patients ages 12 and older with sickle cell disease and a history of vaso-occlusive events. Available at: https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-approval-lyfgeniatm-lovotibeglogene. Accessed December 2025.
  21. European Medicines Agency. Zynteglo. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo. Accessed December 2025.
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  23. Rui L, Prasad MK. Beyond the promise: Evaluating and mitigating off-target effects in CRISPR gene editing for safer therapeutics. Front Bioeng Biotechnol. 2024; 11: 1339189.
  24. BBC News. ‘I feel lucky to get remarkable gene therapy’. Available at: https://www.bbc.co.uk/news/articles/cgmww18jpmeo. Accessed December 2025.
  25. UK Government. The importance of giving patients a voice in the approval of new sickle cell treatment. Available at: https://www.gov.uk/government/case-studies/the-importance-of-giving-patients-a-voice-in-the-approval-of-new-sickle-cell-treatment. Accessed December 2025.

Author: Lia Kisner Ι Porterhouse Pathfinders Intern