ATH‐1105, a small molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP‐43 protein pathology in ALS and frontotemporal dementia‐relevant preclinical models

Abstract Background Frontotemporal dementia (FTD) is a neurodegenerative disorder marked by loss of neurons in the frontal and temporal lobes, leading to cognitive and behavioral changes. Common pathological features include neuroinflammation and intracellular inclusions of TDP‐43, which are found in approximately 50% of people with FTD. Positive modulation of the hepatocyte growth factor (HGF)/MET system has been shown to protect against several drivers of neurodegeneration and may represent a therapeutic strategy for FTD. Here, we assess the effects of ATH‐1105, a small molecule positive modulator of HGF/MET, in preclinical models that capture components of FTD, including neurodegeneration, inflammation, cognitive impairment, and TDP‐43 pathology. Method To evaluate the neurotrophic effects of ATH‐1105, neurite length and synaptic count were measured in rat hippocampal neurons after treatment with ATH‐1105. The neuroprotective effects of ATH‐1105 were assessed in rat cortical neurons subjected to neurotoxic insults including 1‐methyl‐4‐phenylpryidinium, glutamate, lipopolysaccharide (LPS), or hydrogen peroxide. Anti‐inflammatory effects of ATH‐1105 were evaluated by measuring secreted proinflammatory cytokines in LPS‐stimulated THP‐1 differentiated macrophages. To assess pro‐cognitive effects after neuroinflammatory insult, adult mice received a single intraperitoneal injection of LPS followed by daily doses of ATH‐1105 for 14 days. Cognitive performance was assessed in the T‐maze spontaneous alternation task. Finally, Prp‐TDP43 A315T mice, a model of ALS/FTD, were given daily oral treatment with 20 mg/kg ATH‐1105 or vehicle for two months, starting from one month of age. Plasma was evaluated for levels of proinflammatory cytokines and neurofilament light chain. At study termination, TDP‐43 inclusions in the sciatic nerve were measured by immunohistochemistry. Result Treatment with ATH‐1105 increased neurite outgrowth and synaptic count in primary hippocampal neurons and protected against all cytotoxic insults in primary cortical neurons. ATH‐1105 mitigated cytokine release in LPS‐stimulated THP‐1 macrophages and attenuated LPS‐induced cognitive impairment in vivo. In TDP‐43 A315T mice, treatment with ATH‐1105 reduced plasma biomarkers of inflammation and neurodegeneration. Additionally, after two months of treatment, ATH‐1105 reduced intra‐axonal TDP‐43 inclusions in the sciatic nerve. Conclusion The data presented provide preliminary evidence that ATH‐1105 is protective against several pathological mechanisms common to FTD, including TDP‐43 protein pathology, and support its continued evaluation as a therapeutic for FTD.