New gene editing strategy could lead to treatments for people born with inherited diseases of the immune system

A fault in cells that form a key part of the immune system can be repaired with a pioneering gene editing technique, finds new research demonstrated in human cells and mice, led by UCL scientists.

Researchers say the study, published in Science Translational Medicine, could lead to new treatments for a rare disease of the white blood cells that normally help to control the immune system — known as regulatory T cells — and those that protect the body from repeat infections and cancer — known as effector T cells.

Patients with the condition, known as CTLA-4 insufficiency, carry mutations in a gene that cause these T cells to function abnormally. It leads them to suffer from severe autoimmunity, where their immune system attacks their own tissues and organs, including their blood cells.

The condition also hampers their immune system’s ‘memory’, meaning patients can struggle to fight off recurring infections by the same viruses and bacteria. In some cases, it can also lead to lymphomas, a type of blood cancer.

In human cells, using ‘cut’ and ‘paste’ gene editing techniques, using the CRISPR/Cas system, the researchers were able to target the faulty gene in T cells taken from patients with CTLA-4 insufficiency and repair the errors. This restored the levels of CTLA-4 in the cells to those seen in healthy T cells. They were also able to improve symptoms of the disease in mice with CTLA-4 insufficiency by giving them injections of gene edited (corrected) T cells.

Co-senior author, Professor Claire Booth, Mahboubian Professor of gene therapy and paediatric immunology at UCL Great Ormond Street Institute of Child Health, said: “It’s really exciting to think about taking this treatment forward to patients. If we can improve their symptoms and reduce their risk of getting lymphoproliferative disease this will be a major step forward. This particular paper is important because we are using the newest gene editing techniques to precisely correct these T cells, which is a new approach in inborn errors of immunity.”

CTLA-4 is a protein produced by T cells that helps to control the activity of the immune system. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who have only one functional copy produce too little of the protein to sufficiently regulate the immune system.

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