Gene editing approach helps launch first-in-human clinical trial for rare genetic disease

A collaborative effort between investigators at the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) and Massachusetts General Hospital (MGH) demonstrates the potential of precise genome editing technologies, called adenine base editors, to correct disease-causing mutations in stem cells from patients with X-linked chronic granulomatous disease (X-CGD), a rare genetic disorder characterized by high susceptibility to infections.

The findings are published in Science Translational Medicine.

Patients with X-CGD experience recurrent invasive infections, hyperinflammation and inflammatory bowel disease, with increased morbidity and early mortality. The research team sought to optimize gene editing approaches to correct X-CGD mutations and develop a safe and effective treatment for the condition.

The study, which was led by co-first authors Vera Bzhilyanskaya, a postbaccalaureate fellow at NIAID, and postdoctoral research fellow Linyuan Ma, Ph.D., at MGH, was borne out of a longstanding collaboration 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.

“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 noted that adenine base editors may overcome many of the challenges associated with other gene therapy approaches because the treatment is better tolerated by cells compared to Cas9 nuclease-based approaches, since base editors enable correction of the native genomic sequence without permanently introducing new genetic material into cells (so may have diminished risks compared to lentivirus-based gene therapies), and with highly flexible CRISPR-Cas9 enzymes they can access a broader number of target sites and therefore can in principle correct many different genetic mutations.

Based on the team’s findings, a first-in-human clinical trial is now underway to test the potential benefits of base-edited stem cell treatments in patients with X-CGD.