Therapeutic Potential of Fosgonimeton, a Small-Molecule Positive Modulator of the Neurotrophic HGF/MET Pathway, in Neurodegenerative Conditions (S14.008)

Abstract

<h3>Objective:</h3> Evaluate the neurotrophic and neuroprotective effects of fosgonimeton, a small-molecule positive modulator of hepatocyte growth factor (HGF)/MET. <h3>Background:</h3> HGF signaling through the MET receptor promotes neural survival and function, making it a compelling target to combat neurodegeneration. We developed a series of small-molecule positive modulators of HGF/MET, including fosgonimeton, to target this neurotrophic system. <h3>Design/Methods:</h3> To demonstrate the neurotrophic effects of fosgonimeton, primary neurons were treated with the active metabolite of fosgonimeton (fosgo-AM) and assessed for synaptic count and neurite outgrowth. To evaluate neuroprotective effects, primary neurons were treated with fosgo-AM before exposure to relevant neurodegenerative insults, namely oxidative stress (hydrogen peroxide [H₂O₂]), neuroinflammation (lipopolysaccharide [LPS]), excitotoxicity (glutamate), and mitochondrial dysfunction (1-methyl-4-phenylpyridinium [MPP+]). The effects of fosgo-AM on protein aggregation in primary neuron cultures were evaluated via levels of phosphorylated tau (p-tau) induced by amyloid β (Aβ) toxicity in cortical neurons and α-synuclein aggregation induced by 6-hydroxydopamine (6-OHDA) in dopaminergic neurons. In vivo, the therapeutic usefulness of fosgonimeton was assessed for LPS-induced cognitive impairment in mice and 6-OHDA–induced motor deficits in rats. <h3>Results:</h3> In vitro, fosgo-AM significantly increased the number of synapses and neurite length in hippocampal and cortical neurons, respectively. Fosgo-AM was neuroprotective of cortical neurons subjected to oxidative, neuroinflammatory, excitotoxic, and mitochondrial challenges. Significant reduction in the number of disease biomarkers was observed with fosgo-AM treatment, including Aβ-induced p-tau accumulation in cortical neurons and 6-OHDA–induced α-synuclein aggregation in dopaminergic neurons. In vivo, fosgonimeton administration significantly attenuated LPS-induced cognitive impairment and 6-OHDA–induced motor deficits in rodent models. <h3>Conclusions:</h3> These results, from in vitro and in vivo systems, consistently support the broad application of fosgonimeton to neurodegenerative conditions. Collectively, our observations highlight the therapeutic potential of HGF/MET modulation in the management of neurodegenerative diseases that include AD and PD, supporting further clinical exploration of this approach. <b>Disclosure:</b> Dr. Reda has received personal compensation for serving as an employee of Athira Pharma, Inc. . Dr. Reda has stock in Athira Pharma, Inc. . Dr. Taylor has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Taylor has stock in Athira Pharma, Inc.. Dr. Taylor has received intellectual property interests from a discovery or technology relating to health care. Dr. Johnston has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Johnston has stock in Athira Pharma, Inc. An immediate family member of Dr. Johnston has stock in Athira Pharma, Inc. Dr. Johnston has received intellectual property interests from a discovery or technology relating to health care. Dr. Berthiaume has received personal compensation for serving as an employee of Athira Pharma. Dr. Berthiaume has stock in Athira Pharma. An immediate family member of Dr. Berthiaume has stock in Athira Pharma. Dr. Setti has received personal compensation for serving as an employee of Athira Pharma. Dr. Setti has stock in Athira Pharma. Dr. Church has received personal compensation for serving as an employee of Athira Pharma. Dr. Church has stock in Athira Pharma. Dr. Church has received intellectual property interests from a discovery or technology relating to health care.