A first-of-its-kind gene therapy to treat people with CTLA-4 insufficiency, a rare and life-limiting inherited immune disorder, is being advanced through a collaboration supported by LifeArc, a self-funded medical research organisation, and developed by scientists at University College London (UCL), with manufacturing support from NHS Blood and Transplant (NHSBT) and Great Ormond Street Hospital (GOSH).
CTLA-4 insufficiency is a rare genetic condition that disrupts how the immune system is controlled.
CTLA-4 normally acts as a critical “off switch," specifically helping to prevent the overactivation of T cells (a type of white blood cell).
When this mechanism fails, patients can develop a range of symptoms, from bowel inflammation to changes in the numbers of different types of blood cells, which can lead to recurrent infections and significantly reduced life expectancy.
Most people develop symptoms in childhood, with the majority affected before the age of 18.
Current treatments focus on managing these symptoms, such as with immunosuppressive medicines.
In some cases, a bone marrow transplant may offer the hope of a cure by replacing all immune cells, which are produced by bone marrow. But these transplants come with significant risks and are not always possible.
This new therapy takes a different approach by replacing a faulty gene in a patient’s own immune cells. In the lab, scientists can use a tool, often called molecular scissors (CRISPR/Cas9), to remove the faulty gene and replace it with a healthy one. The corrected cells are then returned to the patient to help restore normal function.
The programme will now move through further development and manufacturing ahead of a planned first-in-human Phase I clinical trial in up to 8 patients, aged between one and 65, currently expected to begin in 2028.
Manufacturing and translational development is being supported by NHSBT’s Clinical Biotechnology Centre, part of the LifeArc and Medical Research Council-funded Innovation Hubs for Gene Therapies network, which provides specialist capabilities to accelerate patient access to advanced genetic medicines.
NHSBT will manufacture the AAV6 viral vector used to deliver the corrected gene into the patient’s T cells.
Great Ormond Street Hospital (GOSH) will manufacture the final cell therapy product and act as the sponsor of the clinical trial. GOSH, UCLH and the Royal Free Hospital are expected to serve as clinical sites for patient treatment.
If successful, this approach could offer a long-lasting treatment option, reducing the need for lifelong treatment or bone marrow transplant. It may also help to pave the way for similar treatments in other rare immune disorders.
Commenting on the new therapy, Sam Barrell, CEO at LifeArc, said: “This is an important milestone in advancing a truly innovative therapy for a life-limiting rare disease."
"By supporting this research, we hope to help accelerate the development of an approach that aims to address the underlying cause of the condition, rather than simply manage its symptoms."
“Although further research is needed, advances like this demonstrate the potential of innovative cell and gene therapies to transform outcomes for patients with rare diseases. At LifeArc, we are committed to supporting the translation of promising science into treatments that can make a meaningful difference to people's lives."
