Rethinking Brain Shuttle Targeting Through the Lenses of Human Receptor Variability & Dual-Targeting Strategies

• Profiling TfR, IGF1R, LRP1 and emerging BBB targets across human brain microvessels reveals conserved disease-state expression but high inter-individual variability with potential implications for patient stratification
• Understanding order-of-magnitude variability in receptor abundance and its potential impacts on binding kinetics, target engagement, and dose–exposure relationships for shuttle-enabled therapeutics
• Engineering and benchmarking dual-target brain shuttles to optimize transcytosis efficiency while balancing affinity, valency, and receptor trafficking dynamics
• Evaluating modality-specific considerations for dual shuttles including antibody and oligonucleotide payload delivery, and defining engineering principles to enhance target engagement while avoiding rapid plasma clearance, reduced BBB transport or decreased neuronal uptake

Speakers:

James Gorman

Principal Investigator, Brain Targeting Program

WYSS Institute, Harvard Medical School