The development of a pioneering gene therapy to treat a devastating, rare immune system disorder led by UCL scientists is to move into its next phase after promising early preclinical studies.
CTLA-4 deficiency is a rare disease of the white blood cells that normally help control the immune system – known as regulatory T cells – and those that protect the body from recurrent infections and cancer – known as effector T cells.
It is caused by a lack of the CTLA-4 protein produced by a particular gene – most people have two working copies of this gene, but those with this disorder only have one working copy which means they don’t make enough of the protein to properly regulate their immune system.
The conventional way to treat the disorder is a bone marrow transplant to replace the stem cells responsible for producing the T cells. But transplants are risky and inappropriate for many older, more frail patients.
In recent years, the UCL team has developed a new way of treating the condition: replacing the faulty gene in immune cells with healthy ones, rather than the whole cell.
Early preclinical studies have shown encouraging results, with the corrected cells leading to better regulation of the immune system.
The team’s research is now expected to progress to a planned first-in-human Phase 1 clinical trial in up to eight patients, aged between one and 65, to begin in 2028.
The UCL research is supported by NHS Blood and Transplant (NHSBT) and Great Ormond Street Hospital (GOSH) and funded by the self-funded medical research organization 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 deficiency.
“By correcting the genetic error in the patient’s own T cells, we hope to offer a treatment that addresses the root cause of the disease. This represents an important step forward for patients who currently have very limited options.”
Co-investigator Professor Claire Booth, Mahboubian Professor of Gene Therapy at UCL Great Ormond Institute of Child Health and consultant in pediatric immunology at GOSH, said: “We are committed to advancing breakthrough 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 demonstrates its continued commitment to translating innovative science into clinical benefit.”
The gene-editing approach uses the Nobel Prize-winning CRISPR/Cas9 gene-editing technology to target and cut the defective CTLA-4 gene in half.
A corrected DNA sequence is then delivered to the cell using a modified virus. This is then pasted over the defective part of the gene using a cellular DNA repair mechanism known as homology-directed repair.
This allowed the researchers to maintain important sequences within the CTLA-4 gene – known as an intron – that allow it to be turned on and off by the cell only when needed.
If successful, the new treatment could provide a long-term treatment option, reducing the need for lifelong treatment or a bone marrow transplant, the researchers say. It may also help pave the way for similar treatments in other rare immune disorders, they add.
Chief executive of Immunodeficiency UK Dr Susan Walsh said: “Living with an immunodeficiency such as CTLA 4 deficiency 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 the treatment of a number of other rare immune disorders.”
This is a major milestone in advancing a truly innovative treatment for a rare, life-limiting disease.
While further research is needed, advances like this demonstrate the potential for innovative cell and gene therapies to transform outcomes for patients with rare diseases.”
Sam Barrell, CEO of LifeArc;
Dr Paul Lloyd-Evans, head of the NHSBT Clinical Biotechnology Centre, said: “By supporting this world-leading trial, we hope to save and improve even more lives.”
Professor Booth and co-researcher Professor Emma Morris (UCL Institute of Infection, Immunity & Transplantation) have been supported by the National Institute for Health and Care Research’s Biomedical Research Centers at Great Ormond Street Hospital and University College London Hospitals respectively.
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