Pioneering gene therapy for rare immune disorder shows promise in early pre-clinical studies

The development of a pioneering gene therapy to treat a devastating, rare immune disorder led by UCL scientists is set to move into its next phase following promising early pre-clinical studies.

CTLA-4 insufficiency is a rare disease of the white blood cells that normally help to control the immune system - known as regulatory T cells - and those that protect the body from repeat infections and cancer - known as effector T cells. 

It is caused by a lack of the CTLA-4 protein produced by a specific gene - most people have two working copies of that gene, but those with this disorder have only one functional copy meaning they don't produce enough of the protein to properly regulate their immune system.

The conventional way of treating the disorder is a bone marrow transplant to replace the stem cells responsible for producing the T cells. But transplants are risky and unsuitable in many older, frailer patients.

Over the last few years, the UCL team have been developing a new way of treating the condition: by replacing the faulty gene in the immune cells with healthy ones, rather than the whole cell.

Early pre-clinical studies have shown encouraging results, with corrected cells leading to better regulation of the immune system.

The team's research is now due to progress towards a planned first-in-human Phase One clinical trial in up to eight patients, aged between one and 65, due to begin in 2028.

The UCL-led research is being supported by NHS Blood and Transplant (NHSBT) and Great Ormond Street Hospital (GOSH) and funded by self-funded medical research organisation LifeArc. 

Principal investigator Dr Thomas Fox (UCL Institute of Infection, Immunity & Transplantation) 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."

Co-investigator Professor Claire Booth, Mahboubian Professor in Gene Therapy at UCL Great Ormond Institute of Child Health and a consultant in paediatric immunology at GOSH, said: "We are committed to advancing pioneering cell and gene therapies for children with rare and complex immune diseases.

"By acting as sponsor and manufacturer for this trial, Great Ormond Street Hospital is showing its ongoing commitment to translating innovative science into clinical benefit."

The gene-editing approach uses the Nobel-prize winning gene editing technology CRISPR/Cas9 to target and snip the faulty CTLA-4 gene in two.

Then a corrected sequence of DNA is delivered to the cell using a modified virus. This is then pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.

This allowed the researchers to preserve important sequences within the CTLA-4 gene - known as the intron - that allow it to be switched on and off by the cell only when needed.

If successful, the new therapy could offer a long-lasting treatment option, reducing the need for lifelong treatment or bone marrow transplant, the researchers say. It may also help pave the way for similar treatments in other rare immune disorders, they add.

Immunodeficiency UK chief executive Dr Susan Walsh 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 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."

This is an important milestone in advancing a truly innovative therapy for a life-limiting rare disease.

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."

Sam Barrell, chief executive, LifeArc

Dr Paul Lloyd-Evans, head of the NHSBT Clinical Biotechnology Center, said: "By supporting this world-leading trial, we hope to save and improve even more lives."

Professor Booth and fellow co-investigator Professor Emma Morris (UCL Institute of Infection, Immunity & Transplantation) have been supported by the National Institute for Health and Care Research Biomedical Research Centres at Great Ormond Street Hospital and University College London Hospitals respectively.