New studies reveal the promising capabilities of specialized genome editing tools known as adenine base editors. These tools can rectify genetic mutations responsible for X-linked chronic granulomatous disease (X-CGD) in stem cells derived from affected patients. X-CGD is a rare genetic condition that makes individuals particularly vulnerable to infections.
This research is a joint effort between scientists at the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) and Massachusetts General Hospital (MGH), an integral part of the Mass General Brigham healthcare system. It illustrates how adenine base editors might be used to fix disease-related mutations in stem cells of patients suffering from X-linked chronic granulomatous disease (X-CGD), which is notably marked by a heightened risk of infections. These findings have been detailed in the journal Science Translational Medicine.
X-CGD patients often face regular severe infections, experience hyperinflammation, and may suffer from inflammatory bowel disease, leading to increased illness and early death. The research team aimed to refine gene editing techniques to remedy X-CGD mutations and establish a safe and effective treatment.
The study, spearheaded by co-first authors Vera Bzhilyanskaya, a postbaccalaureate fellow at NIAID, and Linyuan Ma, PhD, a postdoctoral researcher at MGH, originated from a long-term partnership between the laboratories headed by Suk See De Ravin, MD, PhD, a senior research physician at NIAID, and Benjamin Kleinstiver, PhD, who is affiliated with the Center for Genomic Medicine at MGH and is a Kayden-Lambert MGH Research Scholar.
“We’re thrilled about applying base editing to directly amend mutations, as this method differs from traditional gene therapies that work by overexpressing a corrective gene,” stated Kleinstiver. “What we’ve discovered showcases how the enhanced capabilities of engineered CRISPR-Cas9 enzymes can be advantageous and encourages further investigations into using base editors to correct other mutations linked to inherited immune disorders and various diseases.”
Throughout their research, the teams from De Ravin and Kleinstiver collaborated with colleagues to extract hematopoietic stem and progenitor cells from two patients, each with different X-CGD-related mutations, and employed various adenine base editors to address mutations in the CYBB gene. Progenitor cells are specialized stem cells located in bone marrow that can self-replicate and develop into fully formed blood cells. This method proved to be exceedingly effective, achieving more than 3.5 times the efficiency of previous techniques, with minimal unwanted side effects.
The researchers highlighted that adenine base editors might bypass several challenges faced by other gene therapy methods. The treatments are reportedly better tolerated by cells than those based on Cas9 endonuclease, as base editors correct the native genomic sequence without permanently adding new genetic material — which potentially reduces risks compared to lentivirus-based therapies. Furthermore, with versatile CRISPR-Cas9 enzymes, they can target a wider array of genetic sites, allowing for the correction of numerous different mutations.
Building on these insights, the first clinical trial involving patients with X-CGD is currently in progress to explore the potential advantages of base-edited stem cell treatments.
Authorship: Alongside Kleinstiver and Ma, the authors from Mass General Hospital include Lauren R. Fox and Madelynn N. Whittaker.
Disclosures: Kleinstiver and De Ravin have filed a patent related to this research. Kleinstiver is an inventor on patents and applications held by Mass General Brigham concerning genome engineering technologies. Drs. Shengdar Q. Tsai and Cicera R. Lazzarotto are co-inventors of a patent application detailing the CHANGE-seq method. Tsai is part of the scientific advisory board for Kromatid, Twelve Bio, and Prime Medicine. Kleinstiver has provided consultation for EcoR1 Capital, Novartis Venture Fund, and Generation Bio, and serves on several advisory boards including Acrigen Biosciences, Life Edit Therapeutics, and Prime Medicine. Both Tsai and Kleinstiver have financial stakes in Prime Medicine Inc., a company focused on developing therapeutic CRISPR-Cas technologies for gene editing.
Funding: Support came from multiple sources including the National Cancer Institute (75N91019D00024), Massachusetts General Hospital (Executive Committee on Research Fund for Medical Discovery Fundamental Research Fellowship Award), St. Jude Children’s Research Hospital Collaborative Research Consortium on Novel Gene Therapies for Sickle Cell Disease, MGH ECOR Howard M. Goodman Fellowship, Kayden-Lambert MGH Research Scholar award, and various grants from the National Institutes of Health (U01AI176471, P01HL142494, DP2CA281401, Z01-Al-00644, Z01-AI-00645, and Z01-Al-00988), as well as the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases.
