In the first half of 2021, we have had mixed news from the field of gene therapy. March saw a halt in bluebird bio's gene therapy trials after two patients developed serious conditions (acute myeloid leukaemia and myelodysplastic syndrome). The company's investigation concluded that the BB305 lentiviral vector was unlikely to have caused these conditions. However, trials for sickle cell disease and thalassaemia using BB305 have not resumed and sales in the EU—where the treatment is approved for β-thalassaemia—are paused. In the interim, inlaid base editing, an improved CRISPR-based gene editing approach believed to be safer than lentiviral vectors and the classic CRISPR technique has been developed. But where does this new technique fit among the gene therapy options for monogenetic haematological disorders?Despite immense progress in the past decade, efficient and safe delivery to target cells remains the long-standing challenge to successful gene therapy. Important progress has been made using viral vectors, with their refinement leading to the European Medicines Agency's approval for betibeglogene autotemcel in patients with β-thalassaemia in 2019; to an approval request for valoctocogene roxaparvovec for severe haemophilia A in 2019; and to the start of trials of bb1111 for sickle cell disease in 2020. Early trial results are very promising; however, longer-term data are necessary to declare safety (since viruses can potentially randomly insert the genetic material into the patient's genome) and guarantee vector expression levels and efficacy over time.The discovery of the CRISPR-Cas9 genetic scissors by Nobel laureates Emmanuelle Charpentier and Jennifer A Doudna opened a new world of possibilities for gene therapy. In 2019, Victoria Gray became the first patient with sickle cell disease to be treated by CRISPR-Cas9 gene editing as part of a trial. CRISPR-Cas9 has the obvious advantage of being able to make precise, targeted changes to the genome of living cells. However, this precise insertion tool has the risk of persistent expression of the DNA-cleaving enzyme Cas9, which could result in off-target effects. The latest improvement to this technology comes from the aforementioned inlaid base editing; the editing mode of Cas9 is modified to nick only one strand of the DNA double helix and swap in a single nucleotide for another, avoiding breaking the DNA strand in two. Although Cas9 might still cause off-target events, inlaid base editing would avoid double strand breaks that, if misrepaired, can cause chromosomal translocations and start carcinogenic events. This technology would bring a different approach to the clinic, with the aim to correct the causative mutation to achieve therapeutic protein levels that can restore physiological function.Besides technical challenges, a key ethical concern with gene therapy is access, with the field at risk of “becoming a prime example of health care inequity” according to a call to action by the American Society of Gene and Cell Therapy. Given the projected high price for gene therapy—BioMarin hinted that the price tag on its haemophilia A gene therapy could be US $2–3 million, making it the world's most expensive drug—equitable access to gene therapy in high-income countries (HICs) will be challenging. Additionally, as happened with haematopoietic stem-cell transplantation in past decades, organising the intensive hospital care and infrastructure to safely deliver gene therapy in low-income and middle-income countries (LMICs) might mean that some countries will decide not to pursue this treatment option. Therefore, the establishment of an ambitious partnership by Novartis and the Gates Foundation to develop a single-shot gene therapy that would allow expansion of treatment access to resource-constrained areas was an important announcement in February, 2021. This 3 year collaboration with an initial funding of $7·28 million is trying to deliver a gene therapy that can be administered directly into the body, ideally as a single shot. This project could truly revolutionise global health, ensuring access in areas with high disease prevalence, such as sub-Saharan Africa and India, and for underserved minority ethnic groups disproportionally affected in HICs.

Despite recent setbacks, the evolving promise and potential of gene therapy is immense. We are closer to gene therapy becoming standard care for some inherited haematological disorders, such as sickle cell disease, β-thalassaemia, and haemophilia. However, to ensure equitable access, we need to integrate gene therapy as an important goal of the global health agenda. In this inspiring research story, initiatives adapting the technology to expand access to LMICs are a much-needed step towards making a disease-free life possible for all.

For more on inlaid base editing see CRISPR J 2021; 4: 169–77

For more on the call to action by the American Society of Gene and Cell Therapy see Mol Ther 2018; 26: 2715–16

For more on a single-shot gene therapy see EBioMedicine 2019; 42: 3–5

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DOI: https://doi.org/10.1016/S2352-3026(21)00172-1

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