World-first gene therapy to target devastating rare immune disorder

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 prevent 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, for example 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.  

Early pre-clinical studies have shown encouraging results, with corrected cells demonstrating improved control of immune activity. 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 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 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. 
 
“While 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." 

Dr Thomas Fox, Consultant Haematologist and Principal Investigator for the research trial at UCL and UCLH, said: “This is a highly collaborative effort to bring a new therapeutic approach to patients with CTLA-4 insufficiency. By correcting the genetic fault in a patient’s own T cells, we hope to deliver a treatment that addresses the root cause of disease. This represents an important step forward for patients who currently have very limited options.” 

Dr Paul Lloyd-Evans, Head of the NHSBT Clinical Biotechnology Centre, said: “We’re working at the cutting edge of research, using our advanced manufacturing capability to enable complex gene and cell therapies. Producing high-quality viral vectors is a critical step in ensuring safe and effective translation into clinical trials. By supporting this world-leading trial, we hope to save and improve even more lives.” 

Professor Claire Booth, Consultant in Paediatric Immunology at GOSH and Mahboubian Professor in Gene Therapy at UCL Great Ormond Institute of Child Health, said: “Great Ormond Street Hospital is committed to advancing pioneering cell and gene therapies for children with rare and complex immune diseases. Acting as sponsor and manufacturer for this trial reflects our ongoing commitment to translating innovative science into clinical benefit.” 

Dr Susan Walsh, CEO at Immunodeficiency UK, said: “Living with an immunodeficiency like CTLA-4 insufficiency can affect every part of family life, and patients urgently need better options. For our community, this ground-breaking research represents more than scientific progress. It offers hope that the condition could one day be treated at its root.  The therapeutic approach also paves the way for treating a range of other rare immune disorders. Seeing LifeArc support this kind of pioneering work means a great deal to patients and families who have long hoped for better treatment options.” 

MediaCentral Widget Placeholderhttps://mediacentral.ucl.ac.uk/Player/JD21A0GJ

Links

• Dr Thomas Fox's academic profile
• Professor Claire Booth's academic profile
• Professor Emma Morris's academic profile
• UCL Faculty of Medical Sciences
• UCL Translational Resarch Office

Image

Credit: NHS Blood and Transplant

Interested to stay informed of upcoming news, events and funding calls?

• Subscribe to our newsletter and you would automatically become a member of UCL TINs (Therapeutic Innovation Networks) and be the first to receive our event invitations
• Follow us on social media (LinkedIn, Bluesky, X) and stay tuned to our news and updates