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Principal Investigator: Rachita Sumbria
Organization: CHAPMAN UNIVERSITY
Fiscal Year: 2024
Award: $342,000
Funding agency: National Institute on Aging
Project Summary/Abstract
Our application aims to develop a blood-brain barrier (BBB) penetrating erythropoietin (EPO) as a therapeutic
for Alzheimer’s disease (AD) and continues to pursue our long-term goal to develop BBB-penetrable biologics
for central nervous system (CNS) diseases, especially for AD. The rationale to develop EPO as a therapeutic
for AD lies in its ability to modulate several pathways implicated in AD pathogenesis, and its neuroprotective and
neuroregenerative effects. Such a strategy can delay or prevent new brain damage from occurring and potentially
reverse neuronal damage and cognitive decline; anti-Aβ antibodies do not offer such neurotrophic effects. The
main obstacles to the clinical translation of EPO for AD are limited BBB penetration and undesired hematopoiesis
with chronic high EPO doses. For this, we have used a clinically validated BBB drug delivery approach and fused
EPO with a monoclonal antibody (MAb) against the mouse transferrin receptor (TfR) which enters the brain via
BBB TfR-mediated transcytosis and is also rapidly cleared from the systemic circulation owing to the peripheral
TfRs; the latter is expected to minimize hematopoietic side-effects. Our exciting data shows that TfRMAb-EPO
is therapeutic in both a mouse model of amyloidosis and tauopathy. Our proof-of-concept work also shows that
TfRMAb-EPO indeed offers better therapeutic and hematologic indices than EPO in AD mice, however, there
are fundamental questions pertaining to the dose-response, therapeutic-time window, and the safety of TfRMAb-
EPO, that still remain unanswered. Further, a comprehensive investigation of the molecular pathways modulated
by TfRMAb-EPO in the AD brain has not been performed. Based on this, we hypothesize that TfRMAb-EPO is
a disease-modifying therapeutic for AD with better therapeutic and hematologic indices than EPO following
chronic dosing. Therefore, to advance the preclinical development of TfRMAb-EPO for AD, the following specific
aims will be pursued: Aim 1 will determine the efficacy of TfRMAb-EPO in dose-escalation studies, Aim 2 will
examine the safety of TfRMAb-EPO in dose-escalation studies, and Aim 3 will elucidate the molecular pathways
involved in the therapeutic effects of TfRMAb-EPO. We will perform dose-escalation studies in three AD-relevant
mouse models: amyloid precursor protein (APP) overexpressing Aβ mice (APP/PS1), in mice that combine tau
and Aβ pathology (3xTg), and in APPSAA knock-in mice that model AD without APP overexpression. The effect
on key AD pathogenic events (Aβ and tau, microgliosis, neuronal loss, and behavioral deficits), along with an
investigation of TfRMAb-, EPO-, biopharmaceutical- and AD-related adverse events will be studied in young and
aged AD mice. Finally, to gain insights into the molecular pathways modulated by TfRMAb-EPO in the AD brain,
spatial proteomics will be performed. Therefore, Aims 1 and 2 will establish the therapeutic range and time
window of TfRMAb-EPO while Aim 3 will provide mechanistic insights. Overall, the proposal, backed by a strong
scientific premise and data, will provide a clinically feasible and safe approach for sustainable EPO delivery to
the AD brain by utilizing state-of-the-art techniques and mouse models.
Terms: <3xTg><3xTg-AD mice><3xTg-AD mouse><A β-42><A β42><A-beta 42><A-beta42><AD dementia><AD model><Abeta-42><Abeta42><Acquired brain injury><Adverse Experience><Adverse effects><Adverse event><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 therapeutic><Alzheimer's therapeutic><Alzheimers Dementia><Amyloid A4 Protein Precursor><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Protein Precursor><Amyloid beta-42><Amyloid beta-Protein><Amyloid beta-Protein Precursor><Amyloid beta42><Amyloid β><Amyloid β-42><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β-Protein Precursor><Amyloid β42><Amyloidosis><Amyloidβ-42><Amyloidβ42><Antibodies><Autophagocytosis><Autoregulation><Aβ><Aβ-42><Aβ42><BBB penetration><Behavioral><Binding><Biological Agent><Biological Products><Blood - brain barrier anatomy><Blood Plasma><Blood reticulocyte><Blood-Brain Barrier><Body Tissues><Brain><Brain Injuries><Brain Nervous System><CD71><CNS Diseases><CNS disorder><Cell Death><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cellular Proliferation><Central Nervous System Diseases><Central Nervous System Disorders><Chimera Protein><Chimeric Proteins><Chronic><Circulation><Clinical><Clinical Treatment Moab><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Data><Diffusely basophilic erythrocyte><Disease><Disorder><Disturbance in cognition><Dose><Drug Delivery><Drug Delivery Systems><ECSF><Encephalon><Epoetin><Erythropoietin><Event><Fe element><Funding><Fusion Protein><Gliosis><Goals><Hemato-Encephalic Barrier><Hematology><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Histology><Homeostasis><Human><Immune response><Immunological response><Impaired cognition><Investigation><Iron><KI mice><Knock-in Mouse><Knowledge><MT-bound tau><Marrow reticulocyte><Mediating><Metabolic><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Monitor><Monoclonal Antibodies><Movement><Murine><Mus><Nerve Cells><Nerve Regeneration><Nerve Unit><Neural Cell><Neuro-regeneration><Neurocyte><Neurons><Neuroregeneration><Outcome><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Peripheral><Pharmacodynamics><Physiological Homeostasis><Plasma><Plasma Serum><Polychromatophilic Erythrocyte><Primary Senile Degenerative Dementia><Protein Overexpression><Proteomics><Reticulocytes><Reticuloendothelial System, Serum, Plasma><Safety><Synaptic Vesicle P38 Membrane Protein><Synaptic Vesicle Protein P38><Synaptophysin><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Tauopathies><Techniques><Therapeutic><Therapeutic Effect><Time><Tissues><Transferrin Receptor><Transferrin Receptor 1><Work><a beta peptide><abeta><aged><alzheimer model><amyloid beta><amyloid disease><amyloid precursor protein><amyloid-b protein><analog><autophagy><beta amyloid fibril><biologics><biopharmaceutical><biotherapeutic agent><blood cell formation><blood-brain barrier penetration><bloodbrain barrier><bloodbrain barrier penetration><body movement><brain damage><brain-injured><cerebral microbleeds><cerebral microhemorrhage><clinical translation><clinically translatable><cognitive dysfunction><cognitive function><cognitive loss><determine efficacy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><erythrocyte colony stimulating factor><evaluate efficacy><examine efficacy><hematopoietin><hemopoietic><host response><immune system response><immunoresponse><indexing><insight><knockin mice><mAbs><macromolecule><microtubule bound tau><microtubule-bound tau><monoclonal Abs><mouse model><murine model><necrocytosis><nerve cell death><nerve cell loss><nervous system regeneration><neural inflammation><neural regeneration><neuroinflammation><neuroinflammatory><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic tau><neuropathological tau><neuroprotection><neuroprotective><neuroregenerative><novel><overexpress><overexpression><p-tau><p-τ><pathway><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><posttranslational modification of tau><pre-clinical><pre-clinical development><preclinical><preclinical development><prevent><preventing><primary degenerative dementia><regenerated nerve><response><senile dementia of the Alzheimer type><side effect><soluble amyloid precursor protein><stem><tau><tau Proteins><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neuropathology><tau phosphorylation><tau posttranslational modification><tau-1><tauopathic neurodegenerative disorder><tauopathy><transcytosis><τ Proteins><τ phosphorylation>