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Breakthrough gene editing technique can repair faulty T cells in patients with CTLA-4 insufficiency
A mistake in cells that form a key part of the immune system can be repaired using a ground-breaking gene editing technique, new research led by UCL scientists on human cells and mice shows. 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 control the immune system - known as regulatory T cells - and those that protect the body from repeated 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...
Breakthrough gene editing technique can repair faulty T cells in patients with CTLA-4 insufficiency
A mistake in cells that form a key part of the immune system can be repaired using a ground-breaking gene editing technique, new research led by UCL scientists on human cells and mice shows.
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 control the immune system - known as regulatory T cells - and those that protect the body from repeated 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 causes them to suffer from severe autoimmunity, in which their immune system attacks their own tissues and organs, including their blood cells.
The condition also impairs their immune system's "memory," meaning patients can have difficulty fighting off recurring infections from the same viruses and bacteria. In some cases, it can also lead to lymphoma, a type of blood cancer.
In human cells, researchers were able to target the faulty gene in T cells from patients with CTLA-4 insufficiency and repair the errors using “cut and paste” gene editing techniques using the CRISPR/Cas system. This brought the CTLA-4 level in the cells back to the level of healthy T cells. They were also able to improve the 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 Pediatric Immunology at the UCL Great Ormond Street Institute of Child Health, said: "It's really exciting to think about bringing this treatment to patients. If we can improve their symptoms and reduce the risk of lymphoproliferative disease, this will be a big step forward. This particular paper is important because we are using the latest gene editing techniques to achieve this “To precisely correct T cells, which is a new approach to innate immunity defects.”
CTLA-4 is a protein produced by T cells that helps control immune system activity. Most people carry two working copies of the gene responsible for producing CTLA-4, but those who only have one working copy produce too little of the protein to adequately regulate the immune system.
Currently, the standard treatment for CTLA-4 insufficiency is a bone marrow transplant to replace the stem cells responsible for producing T cells. But transplants are risky and require high doses of chemotherapy and many weeks in the hospital. Older patients with CTLA-4 insufficiency are typically not well enough to tolerate the transplant procedure.
Professor Booth said: "There are many positive aspects to our approach. We believe that by correcting the patient's T cells, many of the symptoms of the disease can be improved while being much less toxic than a bone marrow transplant. Cells is simpler and correcting the T cells is easier. With this approach, patients would require much less time in hospital."
The gene editing approach developed by UCL researchers uses the Nobel Prize-winning CRISPR/Cas9 gene editing technology to target the faulty CTLA-4 gene and cut it in two. Then a corrected DNA sequence is delivered to the cell using a modified virus. This is then glued over the faulty part of the gene using a cellular DNA repair mechanism known as homology-directed repair.
This allowed the researchers to obtain key sequences within the CTLA-4 gene - called the intron - that allow it to be turned on and off by the cell only when needed.
Genes that play a crucial role in controlling immune responses are not constantly switched on and are very tightly regulated. The technique we use allows us to leave intact the natural (endogenous) mechanisms that control gene expression while correcting the error in the gene itself.”
Professor Emma Morris,Co-senior author, PProfessor of Clinical Cell and Gene Therapy and Director of UCL's Department of Infection and Immunity
The study was conducted by Dr. Thomas Fox, a Wellcome Trust Clinical PhD Fellow at UCL, led and built on the work of Dr. Pietro Genovese from the Dana-Farber/Boston Children's Cancer and Blood Disorder Center in Boston, Massachusetts, who is one of the authors of the study.
Although CTLA-4 insufficiency is rare, the research team says the gene editing therapy they developed to combat the disease could be a proof-of-principle of their approach that could be adapted to combat other diseases.
Professor Morris added: "It is a way to correct genetic mutations that could potentially be applicable to other diseases. The bigger picture is that it allows us to correct genes that are dysregulated or overactive, but also allows us to understand much more about gene expression and gene regulation."
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Reference:
Fox, T. A., et al. (2022) Therapeutic gene editing of T cells to correct CTLA-4 insufficiency. Science Translational Medicine. doi.org/10.1126/scitranslmed.abn5811.
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