ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with complex pathology, including TDP-43 issues, excitotoxicity, and neuroinflammation.
• Current treatments like riluzole are insufficient, necessitating novel therapeutic strategies.
• ATH-1105, a positive modulator of hepatocyte growth factor (HGF) signaling, has demonstrated preclinical promise for ALS.

Purpose of the Study:

• To investigate the therapeutic potential of ATH-1105 in a TDP-43-driven mouse model of ALS.
• To evaluate ATH-1105 alone and in combination with riluzole.
• To elucidate the mechanism of ATH-1105's neuroprotective effects, focusing on TDP-43 pathology.

Main Methods:

• In vivo studies in Prp-TDP43^A315T transgenic mice treated orally with ATH-1105 and/or riluzole.
• In vitro studies using primary rat spinal motor neurons subjected to glutamate toxicity.
• Assessment of neuroprotection via MET (HGF receptor) knockdown using siRNA.

Main Results:

• ATH-1105 treatment significantly improved neuromuscular function, reduced weight loss, neurodegeneration, and inflammation in ALS mice.
• Combination therapy with ATH-1105 and riluzole yielded superior therapeutic effects compared to monotherapy.
• In vitro, ATH-1105's neuroprotection was linked to MET activation, reduced TDP-43 phosphorylation, and normalized autophagy.

Conclusions:

• ATH-1105 exhibits significant therapeutic potential for ALS, functioning as a standalone treatment or in synergy with riluzole.
• The drug effectively slows neuromuscular deterioration by counteracting neurodegeneration and mitigating TDP-43 pathology.
• ATH-1105 represents a promising candidate for combination therapy in ALS treatment strategies.