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Principal Investigator: Li Gan
Organization: AETON THERAPEUTICS, INC.
Fiscal Year: 2024
Award: $499,911
Funding agency: National Institute on Aging
Abstract
Alzheimer’s disease (AD) is one of the most common in the United States, as the sixth leading cause of death
among those 65 or older, and impairing the quality of life for 6.2 million adults as of late 2020. As the population
ages, the number of AD patients is expected to grow to over 13.8 million by late 2060 without the development
of more effective treatments, straining the capacity of both Medicare and the US caregiving system with the
direct costs of AD estimated at $244B and care-giving estimated to reach $305B by 2050. The primary
biochemical characteristic of AD is the presence of beta-amyloid (Aβ) plaques and neurofibrillary tangles,
primarily composed of hyperphosphorylated tau protein, in the brain. The only FDA approved disease-modifying
treatment for AD is Aduhelm, an anti-Ab monoclonal antibody (mAb) that clears Abeta deposits in the AD brain
despite not significantly improving cognition. However, its approval has boosted other mAb efforts, including
drugs targeting tau tangles, instead of beta amyloid plaques. Aeton has identified ac-tau as a compelling target
for mAb treatment of tauopathy in AD and is developing a mAb based treatment. This pathogenic tau modification
is highly expressed in the AD brain when compared to healthy controls, The lab of Aeton’s co-founder, Dr. Li
Gan, has developed several murine mAbs that strongly bind to the ac-K174 tau protein, effectively reducing
taupathy in mouse models. This reduction protected the hippocampus, a region key for memory and learning,
from typical AD atrophy, reducing cognitive defects in a mouse model of AD. Aeton has licensed these mAbs for
development, humanizing 9 clones to function similarly in human tissue and producing a leading candidate, AT-
01. In this Phase I SBIR application, Aeton has two specific aims: 1) Evaluate the effectiveness of AT-01 in
treating in vitro neural cells and organoids in head-to-head comparisons with another anti-tau mAb, HJ8.7, 2)
Determine the efficacy and safety of AT-01 against HJ8.7 in a mouse model of tauopathy while evaluating its
pharmokinetics and dynamics. At this point, Aeton will evaluate the success of AT-01, determining if it reduces
tauopathy by blocking spread and aggregation via targeting the ac-K174 epitope. In a future Phase II application,
Aeton would then continue evaluation of AT-01 by initiating IND-enabling studies of efficacy and safety. This
Phase I proposal would enable the development of an anti-tau monoclonal antibody treatment for Alzheimer’s
disease, with an eye towards clinical translation.
Terms: <21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD model><Acetylation><Acute><Aducanumab><Adult><Adult Human><Age><Aged 65 and Over><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><American><Ammon Horn><Amyloid><Amyloid (Aβ) plaques><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Antibodies><Antibody Therapy><Antigenic Determinants><Assay><Atrophic><Atrophy><Autoregulation><Aβ><BIIB037><Behavior><Binding><Binding Determinants><Bioassay><Biochemical><Biochemistry><Biological Assay><Biological Chemistry><Blood Plasma><Brain><Brain Nervous System><Caring><Cause of Death><Cell Body><Cells><Cerebrospinal Fluid><Cerebrum><Characteristics><Chronic><Clinical Treatment Moab><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cognition><Cognitive deficits><Collaborations><Cornu Ammonis><Deposit><Deposition><Development><Direct Costs><Disease><Disorder><Dose><Drug Kinetics><Drug Targeting><ELISA><Encephalon><Enzyme-Linked Immunosorbent Assay><Epitopes><Evaluation><FDA approved><Future><Head><Health Insurance for Aged and Disabled, Title 18><Health Insurance for Disabled Title 18><Hippocampus><Homeostasis><Hortega cell><Human><Hybridomas><Immune mediated therapy><Immunoblotting><Immunologically Directed Therapy><Immunotherapy><Impairment><In Vitro><Induced pluripotent stem cell derived human neuron><Induced pluripotent stem cell derived neurons><Inflammatory><Intravenous><Label><Laboratories><Learning><Licensing><MT-bound tau><Measures><Mediating><Medicare><Memory><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Modification><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neurofibrillary Tangles><Neuron from iPSC><Neuron from induced pluripotent stem cells><Neurons><Organoids><Pathogenesis><Peptides><Pharmacodynamics><Pharmacokinetics><Phase><Physiological Homeostasis><Plasma><Plasma Serum><Population><Primary Senile Degenerative Dementia><Proteins><QOL><Quality of life><RNA Seq><RNA sequencing><RNAseq><Recombinants><Research Contracts><Reticuloendothelial System, Serum, Plasma><Role><SBIR><Safety><Senile Plaques><Small Business Innovation Research><Small Business Innovation Research Grant><Synapses><Synaptic><Synaptic plasticity><System><Tauopathies><Testing><Therapeutic><Title 18><Toxic effect><Toxicities><United States><Universities><Washington><Western Blotting><Western Immunoblotting><Work><a beta peptide><abeta><abnormal tau><abnormally aggregated tau protein><above age 65><aduhelm><adulthood><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged><aged 65 and greater><aged 65+><aged ≥65><ages><alzheimer model><amyloid beta><amyloid beta plaque><amyloid-b plaque><amyloid-b protein><antibody based therapies><antibody engineering><antibody treatment><antibody-based therapeutics><antibody-based treatment><assess effectiveness><aβ plaques><beta amyloid fibril><care giving><caregiving><cerebral><cerebral spinal fluid><clinical translation><clinically translatable><cognitive defects><comparable efficacy><comparative efficacy><compare efficacy><cored plaque><cytokine><determine effectiveness><determine efficacy><developmental><diffuse plaque><effective therapy><effective treatment><effectiveness assessment><effectiveness evaluation><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><enzyme linked immunoassay><evaluate effectiveness><evaluate efficacy><examine effectiveness><examine efficacy><filamentous tau inclusion><gitter cell><glial activation><glial cell activation><head-to-head analysis><head-to-head comparison><health insurance for disabled><hiPSC-derived neurons><hippocampal><hippocampal atrophy><hippocampal atropy><human iPSC-derived sensory neuron><human old age (65+)><human tissue><hyper-phosphorylated tau><hyperphosphorylated tau><hypoimmunity><iPS neurons><iPSC derived-neurons><iPSC-derived human neuron><immune deficiency><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunodeficiency><improved><in vivo><induced pluripotent stem cell neurons><inflammation marker><inflammatory marker><mAbs><medical college><medical schools><mesoglia><microglial cell><microgliocyte><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule associated protein tau mutation><microtubule bound tau><microtubule-associated protein tau mutation><microtubule-bound tau><monoclonal Abs><mouse model><murine mAb><murine model><murine monoclonal antibody><mutant tau><mutation in microtubule associated protein tau><mutation in microtubule-associated protein tau><neural inflammation><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuroinflammation><neuroinflammatory><neuronal><neurons derived from induced pluripotent stem cells><neuropathologic tau><neuropathological tau><old age><over 65 years><p-tau><p-τ><paired helical filament of tau><pathogenic tau><pathogenic tau gene mutation><pathological change in tau><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><perivascular glial cell><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><posttranslational modification of tau><prevent><preventing><primary degenerative dementia><programs><protein blotting><school of medicine><self-aggregate tau><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><spatial memory><spinal fluid><success><synapse><tangle><tau><tau PHF><tau Proteins><tau abnormality><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau intronic mutation><tau mediated neurodegeneration><tau mutation><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau pathological change><tau phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><therapeutic target><transcriptome sequencing><transcriptomic sequencing><τ Proteins><τ aggregation><τ mutation><τ phosphorylation><≥65 years>