Overview

Led by UCL, alongside partners including GOSH and NHS Blood and Transplant (NHSBT), this innovative work will develop a novel gene therapy for CTLA-4 insufficiency. The project aims to bring a first-in-human treatment into clinical trial, using gene editing to address the underlying cause of this rare and life-threatening immune condition.

About the partnership

This programme focuses on developing a personalised gene therapy that corrects the faulty CTLA-4 gene in a patient’s own T cells – a type of white blood cell. Scientists take the T cells and use gene editing tools (CRISPR/Cas9) to precisely insert a corrected version, before re-infusing the ‘corrected’ cells back into the body.

Preclinical studies have shown promising results, with the gene-edited T cells improving immune function in the lab and disease symptoms in animal models of the condition.  

The next phase will involve manufacturing the therapy at conditions fit for producing a drug to administer into a human, and then testing it in a small, first-in-human clinical trial involving up to eight patients. The study will assess whether the therapy is safe, whether the corrected cells are able to survive in the body over a period of time and, importantly, signals of whether the therapy can improve symptoms. 

This approach could offer a safer and more targeted alternative, or be used alongside transplant to reduce risks. It may also pave the way for similar treatments for other immune disorders and advance other T cell-based therapies. 

About CTLA-4 insufficiency

CTLA-4 insufficiency is a rare inherited immune condition, part of a group known as inborn errors of immunity. These conditions occur when genetic changes prevent the immune system from working properly.  

CTLA-4 plays a critical role in controlling the immune system, acting as a natural “off switch” to prevent it from becoming overactive. In people with CTLA-4 insufficiency, this control is impaired, leading to a range of serious complications.

People with the condition may experience: 

• frequent or severe infections due to low production of antibodies 
• overactive immune responses causing inflammation, especially of the bowel 
• autoimmune complications, where the body attacks its own blood cells 
• symptoms affecting multiple systems, including the gut, lungs, blood, and nervous system  

There is a clear unmet need for safer, long-term treatments that address the root cause of the condition. Current treatments focus on managing symptoms, such as using antibody replacement or drugs to dampen the immune system. The only potential cure is a bone marrow transplant, but this carries significant risks and is not suitable for all patients.