Researchers of the University College London (UCL) developed a pioneering gene therapy to treat CTLA-4 insufficiency, a rare and serious immune disorder. Initial preclinical studies yielded encouraging results and the team is already planning to move toward a Phase One clinical trial in humans, scheduled for 2028.
The insufficiency of CTLA-4 It is a disease of the white blood cells that affects both regulatory T cells—responsible for controlling the immune system—and effector T cells, which protect the body from repeated infections and cancer. Its origin is in the lack of the CTLA-4 protein: most people have two functional copies of the gene that produces it, but those who suffer from this disorder only have one, which prevents adequate regulation of the immune system.
The conventional treatment is transplantation of bone marrowwhich replaces the stem cells responsible for producing T cells. However, this procedure is risky and is not suitable for many older or frail patients.
The new strategy proposed by the UCL team aims to correct the defective gene directly into the patient’s own immune cells, rather than replacing the entire cell. Initial preclinical studies showed that the corrected cells achieved better regulation of the immune system, the institution indicated in a statement.
Pioneering gene therapy: a key advance in the treatment of CTLA-4 insufficiency
The approach uses CRISPR/Cas9the Nobel Prize-winning gene editing technology, to locate and cut the defective CTLA-4 gene. Then, using a modified virus, a corrected DNA sequence is introduced into the cell. That sequence is integrated into the damaged part of the gene through a cellular repair mechanism known as homology-directed repair.
This method preserves key sequences within the CTLA-4 gene—known as introns—that regulate when the gene is activated or deactivated according to the needs of the organism. cell. It is a relevant technical detail: unlike other gene therapy approaches, here the natural expression logic of the gene is respected.
If successful, the therapy could offer a long-lasting treatment that reduces the need for lifelong treatment or bone marrow transplant. The researchers also note that the approach could pave the way for similar treatments for other rare immune disorders.
The planned clinical trial will include up to eight patients between the ages of 1 and 65. The research is supported by NHS Blood and Transplant (NHSBT) and Great Ormond Street Hospital (GOSH), and is funded by LifeArc, a self-funding medical research organisation.
The main researcher, the Dr. Thomas Fox from the UCL Institute of Infection, Immunity & Transplantation, explained the scope of the advance: «By correcting the genetic fault 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 for patients who currently have very limited options.»
The Dra. Susan Walshchief executive of Immunodeficiency UK, weighed in on the potential impact for those living with the condition: «Living with an immunodeficiency such as CTLA-4 insufficiency can affect every aspect of family life, and patients urgently need better options. For our community, this research offers hope that the condition can one day be treated at its root.»
Sam BarrellCEO of LifeArc, also addressed the significance of the moment: «This is an important milestone in advancing a truly innovative therapy for a rare, life-limiting disease. While more research is needed, advances like this demonstrate the potential of cell and gene therapies to transform outcomes for patients with rare diseases.»
