Gene therapy has delivered life-saving cures that once seemed impossible, yet for much of the world those cures remain out of reach. Photo credit: MJH SHIKDER via Unsplash.
Gene therapy has revolutionised our healthcare technology landscape in less than a century since it was even conceptualised. The earliest experiments to demonstrate that DNA carries information regarding cell structure and function were published in 1944 by Avery, McLeod, and McCarty, in a bacterial transformation experiment. This was a remarkable feat given that neither the structure of DNA, nor the genetic code, would be published for another one or two decades respectively.
Nevertheless, these foundational experiments paved the way for work throughout the 1960s that tested how DNA could be introduced into mammalian cells to alter their function — the essence of gene therapy. In the latter half of the twentieth century, scientists sought to cure genetic diseases with this newfound technology, though they faced many challenges. This ranged from stable integration or expression of DNA into the host cell, to public policy debates.
At last, the vision became realised. In the early 1990s, a little girl who was only four years old, was suffering from severe combined immunodeficiency (SCID). This is a life-threatening condition in which children must be socially isolated due to their increased risk of infection. At the time, the likelihood of a child with SCID reaching their fifth birthday was only 58%.
The world came to know the girl by her name, Ashanti, as she would go on to receive the first ever successful gene therapy treatment. She was given a dose of her own cells which were edited with a retroviral vector, carrying a corrected copy of the adenosine deaminase gene. This treatment would not only save her life but enable her to grow up in community and attend school.
She was given a dose of her own cells which were edited…This treatment would not only save her life but enable her to grow up in community and attend school.
Evolution was now no longer the only player designing our genomes.
Unfortunately, initial progress was slow. These early trials tended to result in high toxicities, either due to inflammatory responses caused by the delivery strategies, or malignancies triggered by oncogenic activation. It wasn’t until 2017 that the Food and Drug Administration (FDA) first approved gene and cell therapies, the first of which was a chimeric antigen receptor T-cell (CAR-T cell) therapy to treat B-cell malignancies. This approach involves the engineering of a patient’s own T-cells to recognise tumour antigens, essentially enabling the patient to mount an immune response against the cancer cells.
It would be an overstatement to claim that gene and cell therapies have solved genetic diseases and cancer, but their impact has certainly altered the therapeutic landscape.
It would be an overstatement to claim that gene and cell therapies have solved genetic diseases and cancer, but their impact has certainly altered the therapeutic landscape. For example, using this CAR-T cell therapy to treat paediatric B-cell acute lymphoblastic leukemia can result in complete remission (no detectable signs of cancer) in 80-90% of patients, though response rates in the treatment of other leukemias were much lower.
Nine years on from these initial approvals, the field of gene therapy is booming. Nevertheless, the development and application of these drugs is not cheap, and somebody must shoulder this cost. A 2023 study reported that the annual spending on gene therapy in the US was $20.4 billion USD. Given the decades of research that has gone into developing these therapies, this cost is hardly surprising, yet it can be limiting.
Fortunately, for those living in the UK, the NHS can support individuals in receiving this radical technology. In November 2023 the gene therapy Casgevy, which treats the inherited blood disorders β-thalassaemia and sickle cell, was approved by the Medicines and Healthcare products Regulatory agency. This approval marked another key milestone — the first drug to actually edit patient genes using CRISPR technology, rather than simply inserting or deleting DNA. Unfortunately, milestone research necessitates expense, with Casgevy having a list price of £1.65 million per patient. Luckily, the NHS can cover this through a confidential discount deal, but this isn’t the case globally.
This enormous cost poses a challenge to the treatment of sickle cell disease and β-thalassaemia due to their global distribution. These disorders derive from incorrect formation of haemoglobin, the protein in our blood responsible for transporting oxygen to our tissues. Intriguingly, having the sickle cell mutation in only one allele can be semi-protective against malaria, leading to its positive selection (increased allele frequency) in malarial regions. For this reason, sickle cell disease is particularly prevalent across sub-Saharan Africa.
Unfortunately, healthcare inequality is exacerbated when it comes to expensive treatments such as gene therapy.
Unfortunately, healthcare inequality is exacerbated when it comes to expensive treatments such as gene therapy. A 2024 study reported that only five gene therapies had been granted approval in low or middle income countries, versus 32 gene therapies granted approval elsewhere. Furthermore, lower income countries are often excluded from clinical trials, therefore disregarding global genetic diversity which may impact treatment efficacy.
As we come to consider the future of gene therapy, it is important to be specific in whose future we are referring to. We are right to be excited for these therapies, and their continual development, having already seen their significant positive impacts. Nevertheless, when looking back across the development of gene therapy, we should consider whether a milestone is truly reached until it is reached for everyone.
Edited by Eva Knightley and Zohar Steinberg.
