A groundbreaking study has shown that next-generation gene editing technology could potentially treat Krabbe disease, a rare genetic disorder.
Severance Hospital announced on Monday that a research team, including Professor Cho Sung-rae from the Department of Rehabilitation Medicine, Professor Bae Sang-soo from Seoul National University School of Medicine, Dr. Nam Bae-geun, and Professor Jeong-hwa Seo from Yonsei University’s Graduate School of Convergence Health and Medical Science, has demonstrated the possibility of controlling the mechanisms behind Krabbe disease through gene correction.
Gene editing is a technique that identifies and modifies specific DNA sequences responsible for diseases. Unlike conventional gene editing methods that cut DNA and correct mutations during repair, the adenine base editing used in this study allows for precise alterations to specific bases without breaking the DNA double helix.
Krabbe disease is a rare genetic disorder that damages the myelin sheath protecting the brain and nerves. It’s caused by mutations in the gene for the enzyme that breaks down galactosylceramide (GALC), a fatty substance. This leads to the buildup of psychosine, a neurotoxic metabolite, making it difficult to form myelin. The resulting damage to the brain’s neural network disrupts signal transmission, causing white matter disorders. Currently, there is no fundamental cure for this condition.
The research team investigated the potential use of adenine base editing (ABE) as a treatment for Krabbe disease.
They injected adenine base editing genes into the brains of mice with Krabbe disease, attempting to replace adenine with guanine. Because the adenine base editor was too large for viral vectors, they delivered it in two parts.
Inside the cells, adhesive proteins reconnected the two pieces. Guided by RNA, the completed base editor moved to the target gene location and corrected the mutated gene.
Five weeks post-treatment, researchers observed activity in the galactosylceramide-degrading enzyme and a reduction in psychosine accumulation. Tissue staining, magnetic resonance imaging (MRI), and electron microscopy confirmed brain myelin recovery. The mice showed improvements in weight, brain mass, and lifespan, with motor functions reaching about 65% of normal levels.
Professor Cho stated that this research demonstrates the potential of adenine base editing as a treatment for Krabbe disease. It believes this technology could pave the way for developing treatments for various rare and intractable genetic disorders.
Professor Bae added that adenine base editing is a safer and more precise gene editing technique compared to traditional methods, as it replaces adenine with guanine without cutting DNA. According to the ClinVar database, about 30% of Krabbe disease patients have mutations that could be addressed by adenine base editing.
The study’s findings were published in the prestigious journal Genome Medicine (Impact Factor 11.2).