Therapeutic Potential of Fosgonimeton, a Small-Molecule Positive Modulator of the Neurotrophic HGF/MET Pathway, in Neurodegenerative Conditions
Sherif Reda1, Robert Taylor1, Jewel Johnston1, Andrée-Anne Berthiaume1, Sharay Setti1, Kevin Church1
1Athira Pharma, Inc.
Objective:
Evaluate the neurotrophic and neuroprotective effects of fosgonimeton, a small-molecule positive modulator of hepatocyte growth factor (HGF)/MET.
Background:
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.
Design/Methods:
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.
Results:
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.
Conclusions:
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.