In 2013, researchers at the MRC Laboratory of Molecular Biology (LMB) in Cambridge identified a mutation in the gene encoding the PI3Kδ enzyme, which plays a critical role in immune cell signalling. This mutation causes the enzyme to become overactive, leading to a rare condition now known as activated PI3-kinase delta syndrome (APDS).
This discovery was made possible through the participation of the Catchpole family, whose members had long suffered from unexplained immune deficiencies. Mary Catchpole’s mother, uncle, and grandmother were all affected by the condition, which had led to repeated infections, autoimmune complications, and early deaths.
Mary’s mother and uncle, who were patients at Addenbrooke’s Hospital, were offered DNA sequencing (whole exome sequencing) to see if there was a genetic cause for their immuno-deficiency. This allowed the research team at the LMB to collaborate closely with researchers from the University of Cambridge, Babraham Institute, and clinicians from Addenbrooke’s to identify the mutation that causes APDS.
The discovery of this genetic cause was a major breakthrough in understanding a previously unexplained group of immune deficiencies. It opened the door to targeted treatment approaches by pinpointing the molecular mechanism behind the disease. This foundational research laid the groundwork for the development of therapies that could directly inhibit the overactive enzyme and restore immune balance.
Building a model to understand the disease
To better understand APDS and test potential treatments, Medical Research Council (MRC) scientists developed a genetically engineered mouse model that carried the same mutation found in human patients. This model was crucial in demonstrating how the overactive PI3Kδ enzyme altered immune cell development and function. It also allowed researchers to test whether inhibiting the enzyme could reverse or mitigate the disease’s effects.
The mouse model showed that PI3Kδ inhibitors could restore more normal immune function, reduce inflammation, and prevent the development of lymphoproliferative disease, an important step toward clinical application. The development of the mouse model provided the vital ‘proof of concept’ for the development of a targeted therapy that could be used to treat APDS.
Clinical trials bring targeted therapy to life
Building on the genetic and preclinical discoveries, researchers collaborated with pharmaceutical partners to develop nemiralisib, a PI3Kδ inhibitor. In 2017, MRC-funded researchers, partnered with GlaxoSmithKline, began clinical trials to test the drug’s safety and efficacy in patients with APDS.
However, its clinical development was halted due to toxicity issues and lack of significant therapeutic benefit. This finding led researchers in the US to explore the use of other PI3Kδ inhibitors, such as leniolisib.
Subsequent clinical trials using leniolisib, which directly targeted the PI3Kδ pathway, showed that it significantly improved immune regulation, reduced lymph node swelling, and improved patients’ quality of life.
Unlike previous treatments for APDS, which included lifelong antibiotics, immunoglobulin replacement therapy, or high-risk bone marrow transplants, leniolisib offered a targeted, less invasive option. It addressed the root cause of the disease rather than just managing symptoms.
NHS approval marks a new era for rare disease care
In 2025, leniolisib became available on the NHS, making the UK the first country in Europe to offer the treatment as standard care. The first patient to receive it was 19-year-old Mary Catchpole from Norfolk, whose family had helped make the original discovery over a decade earlier.
Mary had lived with the condition her entire life, requiring weekly infusions and multiple medications. Her mother, Sarah, died in 2018 at age 43, never having had access to the treatment now available to her daughter. For Mary, the new therapy represents not just a medical breakthrough, but a deeply personal milestone.
She said:
This new treatment is a gift.
It’s bittersweet, because my mum and other family members never got the chance to have this new lease of life. But I feel blessed to have it now.
A full arc of impact: from lab bench to bedside
The journey from genetic discovery to NHS treatment illustrates the full arc of research impact. It began with fundamental science, sequencing DNA, identifying mutations, and modelling disease in animals. It progressed through translational research and clinical trials and culminated in a licensed therapy that is now changing lives.
It also highlights the importance of long-term investment in curiosity-driven biomedical research, alongside the value of patient participation, and the power of collaboration between scientists, clinicians, and families. It is a model for how rare disease research can lead to real-world health benefits.
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