NEW YORK (Reuters Health) – A new compound, NU-9, improved diseased upper motor neurons (UMN) in mice and shows promise for treating amyotrophic lateral sclerosis (ALS) in humans, though more work is needed before a clinical trial can be started, researchers say.

“We identified the first compound that can improve the health of UMNs that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology” – that is, aggregation inside the cell -“two very important underlying causes of motor neuron degeneration,” Dr. Pembe Hande Ozdinler of Feinberg School of Medicine, Northwestern University in Chicago told Reuters Health by email.

“NU-9 has very favorable pharmacokinetic properties, eliminates the ongoing degeneration in vivo, and after 60 days of treatment, the diseased neurons become comparable to their wild-type healthy counterparts,” she said. “Because we have previously shown direct translation at a cellular level, and that UMN in mice and UMN in patients are very similar, we have reasons to believe that NU-9 will also improve the health of diseased UMNs in patients.”

As reported in Clinical and Translational Medicine, Dr. Ozdinler and colleagues conducted a series of experiments in mice and in human postmortem tissue. Among the key findings:

– As Dr. Ozdinler indicated, diseased UMNs in mouse models and patients share common cellular defects, as revealed with electron microscopy.

– NU-9, which underwent multiple rounds of optimization, and was found to cross the blood-brain barrier, penetrate cortical neurons, and have favorable pharmacokinetic properties – e.g., in vitro potency, plasma stability, little inhibition of cytochrome P450s.

– NU-9 treatment (100 mg/kg/day) of diseased mice improved the integrity of mitochondria and the endoplasmic reticulum, reduced misfolded SOD1 in UMNs, significantly improved UMN retention in the motor cortex, and eliminated UMN degeneration in animals with TDP-43 pathology.

– After 60 days of treatment, diseased UMNs became similar to those of healthy controls.

The authors conclude, “This is the first mechanism-focused and cell-based drug discovery study that lays the foundation for studies that will identify compounds based on their ability to restore neuron health, and also reports NU-9 as the first compound that eliminates UMN degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology, an important step in drug discovery efforts for ALS, HSP (hereditary spastic paraplegia), PLS (primary lateral sclerosis), and ALS/FTLD (frontotemporal lobar degeneration) patients.”

Dr. Merit Cudkowicz, Director of the Sean M. Healey and AMG Center for ALS, Chief of Neurology at Mass General, and Director and the Julieanne Dorn Professor of Neurology at Harvard Medical School, called the work “a big step forward for understanding how to treat disorders such as PLS and ALS.”

“People with PLS have UMN loss and currently there are no treatments that slow progression and no great models to screen for treatments,” she told Reuters Health by email. “People with ALS also have UMN involvement, but also have lower motor neuron involvement. It is possible, though unknown, that treatments targeting UMN dysfunction will work both in PLS and ALS.”

Nonetheless, she added, “there remain important steps before NU-9 can enter clinical trials, including toxicology studies to identify any possible safety concerns.”

“The take-home message is that this is an important advance for developing treatments for people who have disorders that involve UMN dysfunction,” she said. “There is a big clinical need. NU-9 is early in development as an investigational treatment and we hope it goes forward successfully.”

Dr. Robert Brown, Director of the Program in Neurotherapeutics at the University of Massachusetts Medical School told Reuters Health by email that the discovery “holds great promise for treating disorders of corticospinal motor neurons, and perhaps other types of neurons as well. It will be exciting to see this move quickly through pre-clinical toxicity testing as a prelude for possible human trials.”

SOURCE: https://bit.ly/3qtjCge Clinical and Translational Medicine, online February 22, 2021.

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