A pioneering collaboration between researchers at the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) and Massachusetts General Hospital (MGH) has demonstrated the potential of advanced genome editing technologies, known as adenine base editors, to rectify disease-causing mutations in stem cells from patients with X-linked chronic granulomatous disease (X-CGD), a rare genetic condition characterized by heightened susceptibility to infections.
Individuals with X-CGD suffer from recurrent invasive infections, hyperinflammation, and inflammatory bowel disease, leading to increased morbidity and early mortality. The research team aimed to optimize gene editing techniques to rectify X-CGD mutations and develop a safe and effective treatment for the condition.
The study, spearheaded by co-first authors Vera Bzhilyanskaya, a postbaccalaureate fellow at NIAID, and Linyuan Ma, Ph.D., a postdoctoral research fellow at MGH, was born out of a longstanding partnership between the laboratories of Suk See De Ravin, MD, Ph.D., a senior research physician and chief of the Gene Therapy Development Unit at the NIAID, and Benjamin Kleinstiver, Ph.D., an investigator at the Center for Genomic Medicine and Department of Pathology at MGH, and Kayden-Lambert MGH Research Scholar.
Benjamin Kleinstiver, Ph.D., expressed his excitement about the use of base editing to directly correct mutations, stating, “Our results showcase the advantages of this approach, which sets the stage for further 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 treated hematopoietic stem and progenitor cells from two patients with distinct X-CGD-causing mutations with various adenine base editors to correct the respective mutations in the CYBB gene. Progenitor cells are stem cells found in bone marrow Transplant that can self-renew and differentiate into mature blood cells. The approach proved highly effective, with an efficiency more than 3.5 times higher than previous methods and minimal off-target effects.
The scientists emphasized that adenine base editors may surmount many of the challenges associated with other gene therapy approaches due to the treatment’s better cellular tolerance compared to Cas9 nuclease-based approaches, as base editors allow for correction of the native genomic sequence without introducing new genetic material into cells (potentially reducing risks compared to lentivirus-based gene therapies), and with highly versatile CRISPR-Cas9 enzymes, they can access a broader range of target sites and, in theory, correct numerous genetic mutations.
Based on the team’s findings, a first-in-human clinical trial is now underway to evaluate the potential benefits of base-edited stem cell treatments in patients with X-CGD.