Research

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons and has no known cause or treatment. It is a refractory disease that mainly develops in late middle age without any obvious trigger, leading to death in several years. In Japan, there are approximately 9,000 ALS patients, but it is not necessarily a rare disease, with approximately 3,000 new patients per year. The disease period (survival period) is very short and the number of patients is consequently quite small. In particular, the prevalence in people older than 60 years is as high as 20 to 30 in 100,000 individuals. Since the disease affects late middle-aged people in their most productive years, it impacts the society significantly. There are great social demands for researchers to determine the disease etiology and develop effective therapies. Despite recent progress in our understanding of the etiology, an effective therapy has not yet been developed.

We are currently the only institute worldwide that is adopting a gene therapy approach for ALS; the approach normalizes the molecular cascade leading to cell necrosis. It is based on the important result that sporadic ALS, which accounts for more than 90% of total cases, is associated with deficient RNA editing in the glutamate receptors of motor neurons, which is necessary in normal conditions.

Currently, there is no radical treatment for ALS.

The only drug approved for ALS is “riluzole” (a glutamate release suppressor), which delays the progress of symptoms and can improve survival by several months. However, the drug has not achieved observable effectiveness. Thus, current ALS treatments focus on symptomatic therapies and care for symptoms that develop in accordance with the disease progress.

We have developed a modified AAV vector that can introduce genes into a wide range of nerve cells in the brain and spinal cord. Using this vector, we are able to deliver a human-derived enzyme-production gene to the motor neurons in the brain and spinal cord to normalize enzyme activity. Thus, we prevent motor neuron death (degeneration and dropping off) and arrest disease progress.

To study the effect of the gene therapy, we incorporated an RNA editing enzyme gene into the AAV vector and intravenously administered it to the model mice that express the abnormal gene associated with sporadic ALS. The transgene was confirmed in spinal motor neurons and the loss of motor function was suppressed. These effects persisted, even after 7 months. Decreases in the number of axons in the vertebral spinal nerve roots and the number of motor neurons were also suppressed. These decreases represent the degeneration and dropping out of motor neurons. Abnormal changes in TDP-43 localization (specific to ALS) also improved, and the number of normal motor neurons increased with TDP-43 localized in the nuclei. None of the mice that received the gene had abnormal glial cell reactions in the central nervous system or inflammatory cell infiltration in the peripheral organs. Accordingly, gene therapy with the AAV vector appears to be safe. This gene therapy that facilitates delivery of a specific normal enzyme to motor neurons broadly and safely using a modified AAV vector is expected to be an innovative therapy for sporadic ALS.