The development of a gene therapy to treat CTLA-4 insufficiency, a rare immune disorder, is set to progress to its next phase following promising early pre-clinical studies, UCL scientists announced on June 27.
CTLA-4 insufficiency affects white blood cells responsible for regulating the immune system and protecting against infections and cancer. The disorder is caused by insufficient production of the CTLA-4 protein due to only one functional copy of the relevant gene. Most people have two working copies, but those with this condition lack adequate protein levels needed for proper immune regulation.
Traditional treatment involves bone marrow transplants to replace stem cells that produce T cells. However, this approach carries risks and may not be suitable for older or frail patients. The UCL team has been developing an alternative method: replacing the faulty gene in immune cells with healthy ones using gene-editing technology rather than transplanting entire cells.
Early studies have shown that corrected cells can better regulate the immune system. The research will now move toward a planned first-in-human Phase One clinical trial involving up to eight patients aged between one and 65 years old, scheduled to begin in 2028. The project is supported by NHS Blood and Transplant (NHSBT), Great Ormond Street Hospital (GOSH), and funded by LifeArc.
Principal investigator Dr. Thomas Fox said, "This is a highly collaborative effort to bring a new therapeutic approach to patients with CTLA-4 insufficiency." He added, "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." Professor Claire Booth said, "We are committed to advancing pioneering cell and gene therapies for children with rare and complex immune diseases." She continued, "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 therapy uses CRISPR/Cas9 technology to target the faulty CTLA-4 gene before delivering corrected DNA via a modified virus using homology-directed repair mechanisms within the cell. Researchers say this allows them to preserve important regulatory sequences within the gene so it can be switched on or off as needed.
If successful, researchers believe this therapy could offer long-lasting treatment options while reducing reliance on lifelong medication or bone marrow transplants.
