AUT00201 boosts muscle strength, coordination in ALS mouse model
Study: Experimental oral small molecule also reduced loss of motor neurons
AUT00201, an experimental oral small molecule being developed by Autifony Therapeutics, reduced the loss of motor neurons — the nerve cells that control movement — and eased motor symptoms in a mouse model of amyotrophic lateral sclerosis (ALS), a new study showed. It was also found to improve muscle strength and coordination.
The company has completed Phase 1a clinical testing (NCT04158453) of AUT00201 in healthy adults, where both single and multiple dosing were found to be safe and well tolerated. A separate trial in adults with epilepsy (NCT05873062) has also been completed.
AUT00201 “may [soon be] tested in additional mouse models of ALS and ultimately in patients,” researchers wrote.
The study, “Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis,” was published in Acta Neuropathologica Communications. It was funded by Autifony.
Researchers find different forms of potassium channel
ALS occurs due to progressive damage to motor neurons. In about half of patients, these cells become overly active — meaning they respond too strongly to stimuli and begin firing signals more readily than normal. This can wear off and damage motor neurons, contributing to muscle weakness and other symptoms of ALS.
AUT00201 is a potassium channel agonist that opens a potassium channel called Kv3 to facilitate the flow of potassium ions out of nerve and muscle cells. The outward flow makes it difficult for these cells to fire signals, helping to stabilize their electrical state. As a result, AUT00201 could reduce nerve cell excitability and slow the progression of the disease.
In this study, an international team led by researchers in Italy set out to understand where these channels are located and if their function is affected in cell and mouse models of ALS. They also tested if activating Kv3 channels in ALS mice had an impact on disease features.
First, they found different forms of the Kv3 channel — Kv3.1, Kv3.3, and Kv3.4 — in both slow- and fast-twitch muscles of healthy mice. Slow-twitch muscles are used for endurance, while fast-twitch muscles are used for bursts of movement. Kv3 channel proteins were more abundant in fast-twitch muscles, increased with age, and stayed high during adulthood.
Kv3.1 and Kv3.4 channels are mostly found in a specific area, called the triad, which helps muscles contract.
AUT00201 treatment did not expand lifespan of mice
To determine whether ALS changes the activity of Kv3 channel genes, the team turned to a mouse model carrying a disease-causing mutation in the SOD1 gene. In these mice, genes for Kv3.1, Kv3.3, and Kv3.4 became less active only at late stages of the disease, suggesting these changes emerge as ALS progresses.
In samples of muscles from patients with sporadic ALS, which arises without a known family history of the disease, the researchers detected only KCNC4, the gene encoding the Kv3.4 channel. Its activity in muscles was reduced by 72% compared with healthy adults.
The researchers then tested AUT00201 — at either 5 mg/kg or 20 mg/kg — against a placebo in the mouse model of ALS. Because Kv3 channel genes are still active in the early stages of the disease, they started treatment early — at 5 weeks old, before the onset of symptoms — and then measured muscle strength and coordination.
[This study] “paves the way for the development of early treatment targeting this family of potassium channels to alleviate symptoms.
While treatment with AUT00201 did not extend the lifespan of mice, it improved muscle strength and coordination. AUT00201 also reduced the loss of motor neurons and the levels of neurofilament light chain, a protein that gets released into the bloodstream when nerve cells are damaged. AUT00201 also reduced inflammation in muscles.
While it is still too early to know whether these findings will apply to patients, this study “paves the way for the development of early treatment targeting this family of potassium channels to alleviate symptoms,” the researchers concluded.
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