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Abstract Details

Targeting Neurotrophic HGF Signaling for the Treatment of Neurodegenerative Disorders
General Neurology
P11 - Poster Session 11 (5:30 PM-6:30 PM)
4-003

To evaluate the potential of small molecules designed to positively modulate hepatocyte growth factor (HGF) activity, a key neurotrophic and neuroprotective signaling system, for therapeutic use in neurodegenerative disorders.
Neurotrophic factor systems, including HGF, are expressed in neurons and glia and play crucial roles in maintaining neuronal survival, connectivity, metabolic stability, and regulating inflammation. Promotion of HGF signaling to enhance these effects may be a promising therapeutic approach in neurodegenerative disorders including Alzheimer’s (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS). We have developed first generation (fosgonimeton) and second generation (ATH-1020 and ATH-1105) small molecules designed to promote neurotrophic HGF system activity, with distinct properties to allow for potential therapeutic application in various neurodegenerative disorders.
To evaluate neurotrophic effects, primary neurons were treated with fosgonimeton, ATH-1020, or ATH-1105 and neurite outgrowth and synaptic count were measured. Neuroprotective effects were assessed in primary neurons (cortical, dopaminergic, or spinal motor neurons) exposed to various insults including amyloid-beta (Aβ1-42), α-synuclein protofibrils, mitochondrial toxins, excitotoxic glutamate, or proinflammatory lipopolysaccharide. In vivo, these compounds were evaluated in models of AD (Aβ1-42 administration), PD (6-hydroxydopamine or α-synuclein administration), and ALS (Prp-TDP43A315T transgenic mice). 
Fosgonimeton, ATH-1020, and ATH-1105 significantly enhanced neurite outgrowth, increased synaptic count, and promoted survival in primary neuron cultures. Neuroprotective effects in vitro were accompanied by a significant decrease in oxidative stress, apoptotic signaling, pathological protein accumulation (pTau, α-synuclein, or TDP-43), and/or lysosomal dysfunction. In vivo, fosgonimeton and ATH-1020 demonstrated significant procognitive effects in AD models, and significantly improved motor function in PD models. In the Prp-TDP43A315T mouse model of ALS, ATH-1105 treatment significantly rescued motor and nerve function. 
These results demonstrate the neurotrophic, neuroprotective, and anti-inflammatory effects of positive modulators of the HGF system. Consistent treatment effects across diverse models of neurodegenerative disorders supports the broad therapeutic potential of targeting neurotrophic HGF signaling.
Authors/Disclosures
Kevin Church, PhD (Athira Pharma)
PRESENTER 		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.
Sherif Reda (Athira Pharma, Inc.) Sherif Reda has received personal compensation for serving as an employee of Athira Pharma, Inc.. Sherif Reda has stock in Athira Pharma, Inc..
Andree-Anne Berthiaume (Athira Pharma) No disclosure on file
Sharay Setti (Athira Pharma) No disclosure on file
Kayla Kleist (Athira Pharma) No disclosure on file
Wei Wu (Athira Pharma Inc.) Wei Wu has received personal compensation for serving as an employee of Athira Pharma. Wei Wu has stock in Athira Pharma.
Robert Taylor (Athira Pharma, Inc.) Robert Taylor has received personal compensation for serving as an employee of Athira Pharma, Inc. Robert Taylor has stock in Athira Pharma, Inc. Robert Taylor has received intellectual property interests from a discovery or technology relating to health care.
Jewel Johnston 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.