A team of researchers led by Professor Haruhisa Inoue (Center for iPS Cell Research and Application, Kyoto University) and Professor Yuishin Izumi (Tokushima University) demonstrated that adenine base editing can correct a disease-causing genetic mutation and alleviate neurodegeneration in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), providing proof of concept for a precision gene therapy for inherited motor neuron diseases.
Motor neuron diseases are progressive neurodegenerative disorders that destroy the nerve cells responsible for movement, often leading to severe disability and premature death. Although many cases arise sporadically, a growing number of inherited forms have been linked to specific genetic mutations, creating new opportunities for targeted therapies. One such disorder is HMSN-P, a rare hereditary disease caused by a mutation in the TFG gene. Patients develop progressive muscle weakness that eventually affects swallowing and breathing, and no disease-modifying treatment is currently available.
The TFG mutation responsible for HMSN-P poses a particular therapeutic challenge because it appears to cause disease through multiple mechanisms. The mutant protein forms abnormal aggregates that damage cells, while disruption of the gene's normal function may also contribute to degeneration. An ideal therapy would therefore correct the mutation itself rather than simply suppressing gene expression.
To address this challenge, the researchers developed a base-editing approach to convert the disease-causing single-nucleotide change back to its healthy form without introducing double-strand DNA breaks. After comparing several candidate adenine base editors in iPS cells generated from an HMSN-P patient, they identified a highly efficient and specific editor capable of correcting the HMSN-P mutation. The researchers delivered the editing system using adeno-associated virus vectors designed to target cells within the spinal cord.
The team then generated a new mouse model carrying the human TFG mutation. These animals developed progressive motor dysfunction, loss of motor neurons, degeneration of nerve fibers, and activation of inflammatory support cells, recapitulating key features of the human disease. Treatment with the base-editing therapy successfully corrected the mutant allele in the spinal cord and produced therapeutic benefits. Treated mice experienced delayed disease onset, improved motor performance, preservation of motor neurons and axons, and significantly extended survival compared with untreated animals.
To better understand how the therapy influenced disease processes, the researchers performed single-cell transcriptomic analyses of spinal cord tissue. They found that the treatment reduced disease-associated immune activation in microglia, the resident immune cells of the central nervous system. Genes involved in antigen presentation and inflammatory signaling were partially normalized, suggesting that correcting the mutation not only protects neurons directly but also improves the surrounding cellular environment.
The investigators also evaluated the therapy in human neuromuscular organoids generated from patient-derived iPS cells. These three-dimensional tissues reproduced important disease characteristics, including abnormal accumulation of TFG protein aggregates and increased neuronal death. Base-editing treatment markedly reduced protein aggregation and suppressed neuronal loss, demonstrating therapeutic effects in a human-derived model system.
While comprehensive safety evaluations will be required before clinical application, the study provides evidence that precise correction of pathogenic single-nucleotide mutations can ameliorate disease progression in hereditary motor neuron disorders. By combining genome editing, patient-derived stem cell technologies, and advanced disease models, this work highlights the potential of precision gene therapies to address the underlying causes of neurodegenerative diseases that currently lack effective treatments.
