Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development and maintained across aging and in an Alzheimer's mouse model.

Abstract

Transferrin receptor (TfR)-targeting of biologics has emerged as a promising strategy to improve drug delivery across the blood-brain barrier (BBB). However, most preclinical studies evaluating TfR-enabled drugs have been conducted in young adult animals. It remains unclear whether age and aging-related diseases impact TfR protein levels and/or BBB transport capacity. Here, we utilized a previously described TfR-targeting antibody transport vehicle (ATV^TfR) to investigate how healthy aging and disease progression in the 5xFAD mouse model of Alzheimer's disease (AD) impact TfR protein and TfR-mediated brain delivery. ATV^TfR transport capacity remained stable across 3- to 24-month-old healthy mice and 5xFAD progression did not impair ATV^TfR brain transport up to 10.5 months, despite significant amyloid burden. Interestingly, neonates exhibited significantly elevated levels of vascular TfR protein and ATV^TfR brain exposure compared to adult mice. Furthermore, vascular TfR in AD patient brains was similar to age-matched controls, suggesting conserved TfR transport is also likely in human AD. Overall, our data demonstrates broad functional utility for TfR-based brain delivery in both healthy aging and in an AD mouse model. Additionally, elevated TfR-mediated brain delivery during early mouse development highlights the potential of added efficacy in utilizing such platforms in disease treatment of infants and children.