Gene Editing for Inherited Motor Neuron Disease Eases Neurodegeneration

A study has found that directly correcting a gene mutation that causes an inherited motor neuron disease can ease neurodegeneration.

According to Aju Life Science on the 21st (local time), a research team led by Professor Haruhisa Inoue of Kyoto University’s Center for iPS Cell Research and Application and Professor Yuishin Izumi of Tokushima University used adenine base editing to restore a disease-causing gene variant to its normal form and reduce neurodegeneration.

HMSN-P, the subject of the study, is a rare inherited disease caused by a mutation in the TFG gene. Patients experience progressive muscle weakness that eventually makes swallowing and breathing difficult, but no treatment currently stops disease progression.

The mutation produces abnormal protein aggregates that damage cells while also interfering with the gene’s normal function. Rather than suppressing gene expression, the research team chose to correct the mutation itself.

The team compared several adenine base editors in patient-derived iPS cells and selected an editor that efficiently corrected the HMSN-P mutation. The editing system was delivered using an adeno-associated virus (AAV) vector designed to target cells in the spinal cord.

The researchers then created a new mouse model carrying the human TFG mutation. The mice recapitulated key features of the human disease, including impaired motor function, motor neuron loss, nerve fiber degeneration and activation of inflammatory support cells.

Mice treated with base editing showed correction of the mutant allele in the spinal cord and delayed disease onset. Their motor function improved, motor neurons and axons were preserved, and survival was significantly longer than in untreated mice.

Single-cell transcriptomic analysis of spinal cord tissue also showed that treatment reduced disease-related immune activity in microglia, immune cells of the central nervous system. Genes related to antigen presentation and inflammatory signaling were partially normalized.

The researchers said this indicates that correcting the mutation not only directly protects neurons but also improves the surrounding cellular environment.

The team also evaluated the treatment in human neuromuscular organoids made from patient-derived iPS cells. These 3D tissues recapitulated disease features, including accumulation of TFG protein aggregates and increased neuronal cell death; after base editing, protein aggregation and neuronal loss were markedly reduced.

The researchers said comprehensive safety assessments are needed before clinical application, but the study provides evidence that precise correction of a pathogenic single-nucleotide mutation could slow progression of an inherited motor neuron disease.

The findings were published in the international journal Molecular Therapy Advances.