Gene Editing Therapy for Rare Immune Disorder Moves Closer to Clinic

Rare Daily Staff

A first-in-class gene therapy targeting CTLA-4 insufficiency, a rare and debilitating immune disorder, is advancing toward clinical testing following encouraging preclinical results from researchers at University College London and collaborators.

The experimental approach aims to correct the underlying genetic defect driving the disease, rather than managing symptoms or replacing entire cell populations.

CTLA-4 insufficiency arises when patients carry only one functional copy of the CTLA-4 gene, leading to impaired immune regulation and increased susceptibility to infections, autoimmunity, and malignancy. Current standard of care relies on allogeneic bone marrow transplantation, a high-risk intervention that is often unsuitable for older or medically fragile patients.

UCL-led researchers have developed a gene-editing strategy that repairs the faulty gene directly within a patient’s own T cells. Using CRISPR/Cas9 technology, the team precisely cuts the defective CTLA-4 sequence and inserts a corrected DNA template via homology-directed repair. The approach preserves native regulatory elements within the gene, enabling physiologic control of CTLA-4 expression—an important distinction from conventional gene addition strategies.

Preclinical studies indicate that edited cells restore more normal immune regulation, supporting advancement to a first-in-human phase 1 trial planned for 2028. The study is expected to enroll up to eight patients ranging in age from one to 65 years. Great Ormond Street Hospital will serve as both sponsor and manufacturer, with additional support from NHS Blood and Transplant and funding from LifeArc, a U.K. philanthropy focused on funding translational research.

“This represents an important step forward for patients who currently have very limited options,” said principal investigator Thomas Fox of the UCL Institute of Infection, Immunity & Transplantation, emphasizing the potential to address disease at its genetic root.

Beyond CTLA-4 insufficiency, researchers and stakeholders see broader implications for the platform. By demonstrating precise, regulated gene correction in immune cells, the strategy could inform treatments for a wider set of rare immunological disorders.

“Advances like this demonstrate the potential of innovative cell and gene therapies to transform outcomes for patients with rare diseases,” said LifeArc CEO Sam Barrell.