Friday, December 27, 2024
12/27/2024
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.
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