SBIR-STTR Award

Aeton Therapeutics is developing inhibitors of cGAS (cyclic GMP-AMP synthase)—a pattern recognition receptor that activates STING and results in the production of interferon (IFN)-ߗas novel therapies for the treatment of Alzheimer’s disease (AD). AD is the most common form of late-onset dementia and affects nearly 50 million people worldwide and an estimated 5.7 million Americans. In 2020, total payments for healthcare, long-term care, and hospice services for people aged 65 and older with dementia were estimated to be $305 billion. The cognitive decline associated with AD correlates with the formation of amyloid ß (Aß) plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Aeton Therapeutics seeks to produce a novel therapeutic for AD by developing cGAS inhibitors (cGASi’s). cGAS is a cytosolic DNA sensing protein that has been linked to a number of neurodegenerative and inflammatory diseases. Upon sensing DNA in the cytosol (due to the presence of pathogens, genomic/mitochondrial damage, or other pathological mechanisms), cGAS catalyzes ATP/GTP coupling to produce 2’3’-cGAMP, a potent ligand of STING, resulting in the production of IFN-ß. Previous studies suggest that cGAS is aberrantly activated in a tauopathy mouse model, resulting in an IFN response and neurotoxic chronic neuroinflammation. In contrast, genetic ablation of cGAS in PS19 mice, which overexpress P301S mutant tau and develop tau pathology and cognitive deficits, protects against those cognitive deficits and the loss of hippocampal synapses. These findings strongly support the development of cGASi’s to protect against the negative effects of cGAS-STING hyperactivation, but existing compounds exhibit only modest potency in inhibiting the cGAS-STING pathway in human THP1 myeloid cells. To develop novel cGASi’s to treat tau-mediated neurodegeneration in AD, in this Phase I project, Aeton Therapeutics proposes the following aims: Aim 1. Develop potent h-cGASi’s via medicinal chemistry of virtual hits 1 and 2. We have identified promising hits via a virtual screen. We will perform optimization and in vitro assessment of h- analogs to identify lead candidates. Aim 2. Determine PK, target engagement, and efficacy of h-cGASi’s in human iPSC-derived microglia and organoid model. The two best leads showing high brain exposure will be assessed in PK studies in wild-type mice and evaluated in human iPSC-derived microglia and organoids. Lead h-cGASi’s must reduce key biomarkers, such as Cxcl4, Ifnb, and TBK1/pTBK1. We expect to identify at least one lead h-cGASi that reduces key biomarkers in cells and organoids, is brain permeable, shows no toxicity in mice, and does not have off-target effects. This will lead to development of novel cGASi’s that are likely to reprogram toxic microglial responses and protect against tau-related cognitive decline.

Public Health Relevance Statement:
Narrative Aeton Therapeutics is developing cGAS inhibitors as novel therapies for the treatment of Alzheimer’s disease (AD), with the goal of blocking a pathway that results in production of interferon-ß and neurotoxic chronic neuroinflammation. AD is the most common form of late-onset dementia, which affects an estimated 5.7 million Americans and has an annual estimated cost of $305 billion. Development of an effective cGAS inhibitor with potent activity in humans has the potential to improve the treatment, survival, and quality of life of the millions of Americans suffering from AD.

Project Terms:
Affect; AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; inhibitor; Biological Assay; Assay; Bioassay; Biologic Assays; Brain; Brain Nervous System; Encephalon; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Cytosol; Disease; Disorder; DNA; Deoxyribonucleic Acid; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Exhibits; Interferon-beta; Endogenous Interferon Beta; Fibroblast Interferon; IFN-Beta; IFN-β; IFNb; Interferon-β; Natural Interferon Beta; Natural human interferon beta; Future; Goals; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Guanosine Triphosphate; GTP; Hippocampus; Ammon Horn; Cornu Ammonis; hippocampal; hospice environment; Hospices; Human; Modern Man; Human Genetics; In Vitro; Interferons; IFN; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Long-Term Care; extended care; longterm care; Medicine; Liver Microsomes; Mitochondria; mitochondrial; Mus; Mice; Mice Mammals; Murine; Persons; Nerve Degeneration; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Organoids; Pathology; Permeability; Drug Kinetics; Pharmacokinetics; Production; Proteins; Quality of life; QOL; Risk; Role; social role; Safety; Synapses; Synaptic; synapse; Toxicology; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid β; Amyloid β-Peptide; Amyloid β-Protein; Aβ; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; tangle; Neurofibrillary Tangles; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; τ Proteins; tau Proteins; health care; Healthcare; Mediating; improved; Chronic; Phase; Series; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; Microglia; Link; analog; p-tau; p-τ; phospho-tau; phospho-τ; phosphorylated tau; post-translational modification of tau; posttranslational modification of tau; tau phosphorylation; tau posttranslational modification; τ phosphorylation; tau-1; Collaborations; Therapeutic; Metabolic; Genetic; Contracts; Contracting Opportunities; Inflammatory; Senile Plaques; Amyloid (Aβ) plaques; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aβ plaques; cored plaque; diffuse plaque; Impaired cognition; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; programs; meter; Late Onset Alzheimer Disease; late onset alzheimer; Dementia; Amentia; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Ablation; Services; American; cytotoxicity; Lytotoxicity; human old age (65+); 65+ years old; Aged 65 and Over; age 65 and greater; age 65 and older; aged 65 and greater; aged ≥65; old age; Toxic effect; Toxicities; Structure; Cognitive deficits; cognitive defects; novel; payment; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Modeling; Property; response; high throughput screening; High Throughput Assay; Quantitative Structure-Activity Relationship; QSAR; Quantitiative Structure Activity Relationship; Myeloid Cells; Genomics; drug discovery; Tauopathies; neuropathologic tau; neuropathological tau; tau associated neurodegeneration; tau associated neurodegenerative process; tau induced neurodegeneration; tau mediated neurodegeneration; tau neurodegenerative disease; tau neuropathology; tauopathic neurodegenerative disorder; tauopathy; Molecular Interaction; Binding; TBK1 gene; FLJ11330; NF-Kb-Activating Kinase Gene; T2K; TBK1; Data; Research Contracts; in vivo; Wild Type Mouse; wildtype mouse; Pathologic; Preparation; preparations; Docking; Therapeutic Effect; Development; developmental; Pattern recognition receptor; Pathway interactions; pathway; hyper-phosphorylated tau; hyperphosphorylated tau; virtual; abnormal tau; microtubule associated protein tau mutation; microtubule-associated protein tau mutation; mutant tau; mutation in microtubule associated protein tau; mutation in microtubule-associated protein tau; pathogenic tau; pathogenic tau gene mutation; pathological change in tau; tau abnormality; tau intronic mutation; tau pathological change; τ mutation; tau mutation; neural inflammation; neuroinflammatory; neuroinflammation; designing; design; pathogen; Coupling; neurotoxic; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; amyloid assembly; amyloid formation; murine model; mouse model; iPS; iPSC; iPSCs; induced pluripotent cell; inducible pluripotent stem cell; induced pluripotent stem cell; overexpress; overexpression; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; bio-markers; biologic marker; biomarker; Biological Markers; in vitro activity; Genetic study; nano-molar; nanomolar; clinical candidate; Innate Immune Response; recruit; cGAMP STING; cGAMP-STING; cGAMP/STING; cGAS/STING; cyclic GMP-AMP synthase/STING; Stimulator of Interferon Genes; lead candidate; in silico; Alzheimer's therapeutic; Alzheimer's disease therapeutic; cost estimation; cost estimate; STING agonists