Gene Therapy Targeting Neuromuscular Junctions Could Alleviate ALS

Using gene therapy, scientists in Japan have slowed muscle degeneration and prolonged life in a mouse model of amyotrophic lateral sclerosis.

AsianScientist (July 26, 2017) – In a study published in the journal EMBO Molecular Medicine, a group of researchers from the University of Tokyo describe a treatment method that prolonged the lives of mice with symptoms of amyotrophic lateral sclerosis (ALS).

ALS, also known as Lou Gehrig’s disease, is a neurodegenerative disorder of motor neurons characterized by the severe deterioration of muscle. The degeneration and loss of neuromuscular junctions (NMJs)—the essential chemical synapses that transfer control signals from motor neurons to skeletal muscles—lead to the loss of motor function, including the ability to breathe. However, therapies that protect or restore NMJs remain elusive.

The research group led by Professor Yuji Yamanashi and Dr. Sadanori Miyoshi at the Institute of Medical Science at the University of Tokyo, together with collaborators, had previously discovered that the muscle protein known as docking protein 7 (Dok-7) is essential for forming NMJs. Mutations in the related human DOK7 gene cause DOK7 myasthenia, a hereditary disease characterized by a defective NMJ structure.

In the current study, the research group found that by restoring the expression of DOK7 using gene therapy in a mouse model of ALS, the loss of motor nerve terminals was suppressed, resulting in larger NMJs which slowed the progression of muscle atrophy. Importantly, mice treated with this method before the onset of ALS-like symptoms had an average life span of 166.3 days compared with 154.4 days for non-treated mice. After the onset of ALS-like symptoms, the treatment prolonged the duration of survival to an average of 64.2 days compared with 50.3 days in non‐treated mice.

The findings suggest that therapeutic approaches aimed at enlarging NMJs might be useful in developing treatments for ALS and other types of motor neuron diseases associated with abnormal development of NMJs. Age-related ailments like sarcopenia, which are likely to become a growing concern in aging societies, could also benefit from such treatments.

“This study originates from a finding in basic, biological research, which had no particular disorder as a target; the current outcome was obtained through the participation of numerous collaborators—both basic researchers and clinical researchers—and the huge support from multiple public grants,” said Yamanashi.

“By acknowledging the huge contributions of our collaborators and supporters, we would like to do our best to understand the causes of ALS and other intractable disorders, with the aim of developing effective therapies.”

The article can be found at: Miyoshi et al. (2017) DOK7 Gene Therapy Enhances Motor Activity and Life Span in ALS Model Mice.


Source: University of Tokyo; Photo: Shutterstock.
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