Pioneering CRISPR Gene Therapy for CTLA-4 Insufficiency Advances Toward First-in-Human Trial
核心洞察
UCL scientists are developing a first-of-its-kind gene therapy for CTLA-4 insufficiency (搜索), a rare inherited immune disorder with limited treatment options.
The approach uses CRISPR/Cas9 to replace the faulty CTLA-4 (搜索) gene in patients' own T cells, addressing the root cause rather than managing symptoms.
Early pre-clinical studies show corrected cells lead to better immune regulation, with a Phase I trial in up to 8 patients planned for 2028.
A pioneering gene therapy for CTLA-4 insufficiency (搜索), a rare and life-limiting inherited immune disorder, is advancing toward clinical development following promising early pre-clinical results, scientists at University College London (UCL) have announced. The therapy, which employs Nobel Prize-winning CRISPR/Cas9 gene-editing technology, represents the first treatment approach designed to correct the underlying genetic cause of the disease rather than merely managing its symptoms.
The program is now progressing through further development and manufacturing ahead of a planned first-in-human Phase I clinical trial in up to eight patients, aged between one and 65, currently expected to begin in 2028. The effort is supported by NHS Blood and Transplant (NHSBT), Great Ormond Street Hospital (搜索) (GOSH), and funded by the self-funded medical research organization LifeArc (搜索).
Understanding CTLA-4 Insufficiency (搜索)
CTLA-4 insufficiency (搜索) is a rare genetic condition that disrupts how the immune system is controlled. The CTLA-4 (搜索) protein normally acts as a critical "off switch," specifically helping to prevent the overactivation of T cells. When this mechanism fails, patients can develop a range of symptoms, from bowel inflammation to changes in the numbers of different types of blood cells, which can lead to recurrent infections and significantly reduced life expectancy.
The disease is caused by a lack of the CTLA-4 (搜索) protein produced by a specific gene. While most people have two working copies of that gene, those with this disorder have only one functional copy, meaning they do not produce enough of the protein to properly regulate their immune system. Most people develop symptoms in childhood, with the majority affected before the age of 18.
Current treatments focus on managing symptoms, such as with immunosuppressive medicines. In some cases, a bone marrow transplant may offer the hope of a cure by replacing all immune cells produced by bone marrow, but these transplants come with significant risks and are not always possible, particularly in older, frailer patients.
A Gene-Editing Approach to the Root Cause
The UCL team's therapy takes a fundamentally different approach: replacing the faulty gene in a patient's own immune cells rather than replacing the whole cell. The gene-editing strategy uses CRISPR/Cas9 to target and snip the faulty CTLA-4 (搜索) gene in two. A corrected sequence of DNA is then delivered to the cell using a modified virus — specifically, an AAV6 viral vector manufactured by NHSBT's Clinical Biotechnology Centre. This corrected sequence is pasted over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.
Critically, this approach allowed the researchers to preserve important sequences within the CTLA-4 (搜索) gene — known as the intron — that enable the gene to be switched on and off by the cell only when needed. Early pre-clinical studies have shown encouraging results, with corrected cells leading to better regulation of the immune system.
Collaborative Infrastructure and Clinical Path
The manufacturing and translational development is being supported by NHSBT's Clinical Biotechnology Centre, part of the LifeArc (搜索) and Medical Research Council-funded Innovation Hubs for Gene Therapies network, which provides specialist capabilities to accelerate patient access to advanced genetic medicines. GOSH will manufacture the final cell therapy product and act as the sponsor of the clinical trial. GOSH, UCLH, and the Royal Free Hospital are expected to serve as clinical sites for patient treatment.
Principal investigator Dr. Thomas Fox of the UCL Institute of Infection, Immunity & Transplantation described the effort as "a highly collaborative effort to bring a new therapeutic approach to patients with CTLA-4 insufficiency (搜索)." 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."
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, emphasized the institutional commitment: "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 (搜索) is showing its ongoing commitment to translating innovative science into clinical benefit."
Broader Implications for Rare Immune Disorders
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.
Dr. Susan Walsh, chief executive of Immunodeficiency UK, underscored the patient community's perspective: "Living with an immunodeficiency like CTLA-4 insufficiency (搜索) 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."
Sam Barrell, chief executive of LifeArc (搜索), called the development "an important milestone in advancing a truly innovative therapy for a life-limiting rare disease," adding that "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."
Dr. Paul Lloyd-Evans, head of the NHSBT Clinical Biotechnology Center, noted: "By supporting this world-leading trial, we hope to save and improve even more lives." Professor Booth and fellow co-investigator Professor Emma Morris have been supported by the National Institute for Health and Care Research Biomedical Research Centres at Great Ormond Street Hospital (搜索) and University College London Hospitals respectively.