A joint research team from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) and Massachusetts General Hospital (MGH) has successfully used a novel gene-editing technique to correct disease-causing mutations in stem cells from patients with X-linked chronic granulomatous disease (X-CGD). This breakthrough could lead to a new gene therapy for treating a number of diseases. The findings, published in Science Translational Medicine, showcase the promising potential of adenine base editors for treating genetic diseases.
X-CGD is a rare genetic disorder that primarily affects males. It is caused by a mutation in the NOX2 gene, which is located on the X chromosome. This gene provides instructions for making a protein called NADPH oxidase, which is essential for the immune system to fight off infections.
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While there is no cure for X-CGD, treatment focuses on managing symptoms and preventing infections.
“We’re excited about the use of base editing to directly correct mutations since this approach is distinguished from traditional gene therapies that overexpress a corrective gene,” said Kleinstiver. “Our results demonstrate how the improved capabilities of engineered CRISPR-Cas9 enzymes can be beneficial, and together motivate additional studies using base editors to correct other mutations that cause inborn errors of immunity and other diseases.”
In their research, the De Ravin and Kleinstiver laboratories and colleagues took hematopoietic stem and progenitor cells from two patients with different X-CGD-causing mutations, and then treated the cells with various adenine base editors to correct either mutation in the CYBB gene. Progenitor cells are stem cells found in bone marrow that can self-renew and differentiate into mature blood cells. The approach was highly effective, with an efficiency of more than 3.5 times higher than previous approaches and with minimal off-target effects.
The scientists highlighted the advantages of adenine base editors over traditional gene therapy methods. These editors are more cell-friendly than Cas9 nuclelease-based approaches, as they can correct genetic mutations without introducing foreign DNA. Additionally, their versatility allows them to target a wider range of genetic sequences, making them potentially suitable for correcting numerous genetic disorders.
