Efficient brain delivery of neuroprotective antibodies
First, we will evaluate the time-dependent concentrations of our neuroprotective antibody in the brains of mice to optimize intravenous dosing. Next, we will evaluate the levels of neuroprotective receptor activation as a function of time to further optimize dosing to maintain receptor activation over therapeutically relevant timescales. Finally, we will evaluate off-target impacts of receptor activation outside the brain to identify the maximum tolerated doses.
The most innovative aspect of our proposal is the development of a bispecific antibody that efficiently penetrates the blood-brain barrier and induces neuroprotective signaling. Our approach targets an understudied transport pathway into the brain, which leads to extended brain retention and enhanced neuroprotective receptor activation. We expect our research will improve the delivery of diverse therapeutic antibodies to the brain, which is broadly important for treating disorders ranging from neurodegenerative diseases (Alzheimer’s, Parkinson’s and dementias) to brain cancer, stroke and mental disorders. We also expect this research will critically evaluate the potential for safely activating neuroprotective receptors in the brain without inducing off-target toxicity.