Diabetes was first recorded in the 5th century BCE, recognised by the characteristic ‘sweet urine’ of affected individuals. However, it wasn’t until 1922 that the discovery of exogenous insulin transformed type 1 diabetes (T1D) from a fatal diagnosis into a manageable condition.1 More than a century later, we now understand that the disease is driven by an autoimmune attack on pancreatic β-cells, leading to the loss of endogenous insulin and the lifelong need for insulin replacement.
Today, approximately 400,000 people in the UK live with T1D,2 and its incidence continues to rise. While insulin therapy has evolved far beyond the days of cow pancreas-derived insulin and urine dipsticks, people living with T1D remain entirely dependent on exogenous insulin for blood glucose control. Yet, insulin’s narrow therapeutic window presents challenges: fluctuations in blood sugar levels increase the risk of both hypoglycaemia and hyperglycaemia, contributing to serious complications, such as retinopathy and neuropathy,3 highlighting the urgent need for alternative therapies.
NOVEL APPROACHES TO MANAGEMENT
'In the last decade, cell-replacement therapies that use stem cell-derived islets (SC-islets) have become a reality.'
Preventative strategies have shown promise: teplizumab, a drug approved by the US Food and Drug Administration, is able to delay the onset of T1D by up to three years.4 However, preventative drugs must be administered during T1D onset, limiting their use to those still within the ‘honeymoon period’ post-diagnosis.
For others living with T1D, replacing lost β-cells presents a potential solution to eliminate insulin dependence and its associated risks. In 2000, islet transplantation gained traction when James Shapiro’s team improved outcomes using steroid-free immunosuppression.5 However, donor shortages remain a challenge.
In the last decade, cell-replacement therapies that use stem cell-derived islets (SC-islets) have become a reality. Notably, Douglas Melton and Timothy Kieffer’s teams independently pioneered protocols to generate insulin-responsive β-cells in vitro. Melton’s protocol was commercialised, with the refined cells used in Vertex’s clinical trials: VX-880, which delivers SC-islets via hepatic infusion with ongoing immunosuppression, and VX-264, which uses an encapsulation device to protect transplanted SC-islets from immune attack.6,7 Justifiably, Melton, a father of two children living with T1D, was named one of Time magazine’s 100 most influential people in 2009. Yet, significant challenges remain for cell-replacement therapies. How can we reliably generate these cells at a scale that can help thousands? How can we protect them from the immune system? How do we ensure that they can integrate into the body and efficiently vascularise?
Addressing these challenges will require integration of cell engineering, immunomodulation, vascularisation and encapsulation, needing collaboration from specialists across the breadth of UK scientific research. Non-specialised laboratories face significant challenges in generating quality-controlled SC-islets, due to the labour-intensive nature of these protocols and a lack of the specialised expertise that is required.
PROGRESS IN THE UK
Cryopreserved SC-islets produced by BetaCell Birmingham display insulin promoter-driven green fluorescent protein expression.
Across the pond, Canada and the USA lead cell-replacement therapies for T1D. Despite its powerhouse status in research, the UK is somewhat falling behind. Nevertheless, there is much reason to remain optimistic. In the past decade, Francesca Spagnoli and Rocio Sancho’s teams at King’s College London pioneered the production of SC-islets in the UK. This was soon followed by the Akerman lab, and the establishment of BetaCell Birmingham, an academic facility that aims to produce SC-islets for UK researchers, enabling them to overcome the fundamental barriers faced by cell-replacement therapies.
BetaCell Birmingham is already shaping the landscape of cell-replacement therapies in the UK, through its strategic interdisciplinary collaborations with bioengineers and islet biologists at Imperial College London and Oxford University. Having developed its own 3D organoid protocol, BetaCell Birmingham is now set to produce up to 10 billion SC-islets simultaneously with the purchase of a new bioreactor funded by NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research), aiming to position UK researchers on a par with their North American peers.
What’s next for the UK? Vertex has already invested $0.5 billion in its cell-replacement therapies – a sum that will need to be recouped within the lifespan of its intellectual property (IP) licence. Can the NHS afford to cover the cost of cell-replacement therapy? Unless Wes Streeting performs a miracle, the UK will need to step up and produce its own SC-islets, either by patenting new technology, or by swiftly acquiring the capacity to produce SC-islets once they become ‘generic medicine’, following the expiration of IP. This is no easy feat, as the cells must comply with all relevant guidelines while being produced at a large scale – trillions at a time – something that is currently only achievable at a single Catapult facility in the UK.
Thankfully, the Steve Morgan Foundation has recently given the T1D therapy field in the UK a much-needed boost with a £50 million injection. Let’s hope this enables more UK researchers to study SC-islets, sparks more patents in the field, and supports the UK’s capacity to supply SC-islets for the NHS when the time comes…
JESSICA E HIBBERT, JUNYUE HUANG AND ILDEM AKERMAN
Department of Metabolism and Systems Science, School of Medicine and Health, University of Birmingham
REFERENCES
1. Karamanou M et al. 2016 World Journal of Diabetes https://doi.org/10.4239/wjd.v7.i1.1.
2. Ng SM et al. 2023 World Journal of Diabetes https://doi.org/10.4239/ wjd.v14.i8.1194.
3. Garofolo M et al. 2019 Cardiovascular Diabetology https://doi.org/10.1186/s12933-019-0961-7.
4. Ramos EL et al. 2023 New England Journal of Medicine https://doi.org/10.1056/nejmoa2308743.
5. Shapiro AM et al. 2000 New England Journal of Medicine https://doi.org/10.1056/nejm200007273430401.
6. Rezania A et al. 2014 Nature Biotechnology https://doi.org/10.1038/nbt.3033.
7. Pagliuca FW et al. 2014 Cell https://doi.org/10.1016/j.cell.2014.09.040.
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