Correction of ATM-deficiency by gene transfer with a split intein dual vector system

Ataxia–telangiectasia (A-T) is a rare, inherited, life-limiting multisystem disorder caused by mutations in the ATM gene, which plays a central role in the cellular DNA damage response. Patients with A-T develop progressive neurodegeneration, severe immunodeficiency, recurrent infections, and a markedly increased cancer risk. There is currently no curative treatment, and management remains purely supportive. The increasing incidental detection of A-T through TREC-based newborn screening raises clinical and ethical concerns further underscoring the urgent need for an effective early intervention.

This project aims to develop a one-time, autologous hematopoietic stem cell (HSC) gene therapy to restore functional ATM protein and correct immune dysfunction in A-T patients. Because the ATM gene is too large for conventional viral vectors, the project applies an innovative dual-vector strategy based on split intein–mediated protein trans-splicing. This approach delivers the gene in two parts that reassemble into a full-length, functional protein inside the patient’s cells.

The research will optimize this platform in vitro and evaluate its therapeutic efficacy and safety in a well-established preclinical mouse model. By restoring ATM activity in blood-forming stem cells, the goal is to rebuild immune competence, reduce cancer risk, and significantly improve survival. Beyond A-T, this work establishes a broadly applicable gene therapy platform for delivering oversized genes - overcoming a major technological barrier in the field and opening new treatment possibilities for other currently untreatable genetic diseases.