Scientists identify compound to reverse neuron damage from ALS

For the first time, scientists have identified a compound to repair amyotrophic lateral sclerosis (ALS) neuron damage.

Scientists at Northwestern University have identified the compound that is able to reverse the degeneration of upper motor neurons that become diseased, and which are a key contributor to ALS – a fatal neurodegenerative disease that causes paralysis.

In ALS, movement-initiating nerve cells in the brain known as upper motor neurons and muscle-controlling nerve cells in the spinal cord known as lower motor neurons die, resulting in rapidly progressing paralysis and death. Currently, there is no treatment for the brain component of ALS, and no drug for hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) – conditions also caused by neuron degeneration.

Senior author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine, said: “Even though the upper motor neurons are responsible for the initiation and modulation of movement, and their degeneration is an early event in ALS, so far there has been no treatment option to improve their health. We have identified the first compound that improves the health of upper motor neurons that become diseased.”

The study has been published in Clinical and Translational Medicine.

Finding a target for therapy

Study author Richard Silverman, of the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern University, identified a compound, NU-9, developed in his lab for its ability to reduce protein misfolding in critical cell lines which initiated the study. The compound is non-toxic and crosses the blood brain barrier.

The NU-9 compound addresses two of the important factors that cause upper motor neurons to become diseased in ALS which are protein misfolding and protein clumping inside the cell. Proteins fold in a unique way to function and when they misfold they become toxic to the neuron. Sometimes proteins aggregate inside the cell and cause pathology as in the TDP-43 protein pathology. This happens in about 90% of all ALS patients’ brains and is one of the most common problems in neurodegeneration.

The research team began to investigate whether NU-9 would be able to help repair upper motor neurons that become diseased due to increased protein misfolding in ALS, showing positive results in animal models.

Reversing damage to neurons

After administering NU-9, the scientists discovered that both the mitochondria and the endoplasmic reticulum began to regain their health and integrity resulting in improved neuron health.

They found that the upper motor neurons were more intact and stopped degenerating so much that the diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.

“Improving the health of brain neurons is important for ALS and other motor neuron diseases,” said senior author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine.

Ozdinler and colleagues will now complete more detailed toxicology and pharmacokinetic studies prior to initiating a Phase I clinical trial.