Objective/Rationale:
Immunotherapy using antibodies directed against alpha-synuclein is an extraordinarily promising, potentially disease-modifying treatment approach for Parkinson’s disease (PD). However, achieving reliable, chronic central nervous system (CNS) delivery for macromolecules such as antibodies has been a major unmet challenge. The goal of this research is to determine the brain delivery and distribution of antibodies and antibody fragments following intranasal administration, with a particular focus on brain areas where alpha-synuclein aggregrates (Lewy bodies and neurites) first appear.
Project Description:
We will determine brain levels of large monoclonal antibodies (full-length immunoglobulin G) and smaller antibody fragments following intranasal application in pre-clinical models. We will use different doses of several antibody forms labeled with either a radioactive or fluorescent label and deliver them as drops to models with and without a novel, physiologic absorption enhancer that we have recently identified. Brain, blood and peripheral tissue levels will be measured and mapped using multiple technologies. Control experiments will be performed to assess brain levels and distribution following systemic input of the various antibody forms in order to assess the targeting efficiency of the intranasal route compared to intravascular application with matched doses.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This project will allow us to obtain critical, quantitative central and systemic distribution data for intranasally applied antibodies, establish the feasibility of such a strategy for PD immunotherapy, and help in dose finding/adjustment for future studies using pre-clinical models. Delivering antibodies capable of binding alpha-synuclein and clearing it from the brain could potentially neutralize, prevent or perhaps even reverse the Lewy pathology and neurodegeneration that are the hallmarks of this devastating disease.
Anticipated Outcome:
This is a proof-of-concept study to determine whether intranasal immunotherapy holds promise as a non-invasive treatment strategy for Parkinson’s patients. Currently, antibodies are administered as in-patient infusions or out-patient injections that result in high serum levels but uncertain brain exposure. The development of a needle-free drug delivery strategy targeting antibody therapeutics to the brain would be a considerable advance. The outcome of this study is expected to move us toward that goal.
Final Outcome
Our study shows that intranasally applied full length antibodies may be successfully targeted to the brain of pre-clinical models and achieve levels in multiple brain areas that might be expected to have effects. Antibody levels across all brain areas sampled following intranasal administration were substantially higher than levels detected following matched intravascular dosing of antibody, suggesting at least some portion of intranasal antibody delivery to the brain occurred via a direct pathway not involving absorption into the bloodstream. Intranasal application of a novel, physiologic absorption enhancer leads to higher antibody levels being detected in certain brain areas. Furthermore, intranasal application of over 10-fold higher antibody amounts led to over 10-fold higher antibody levels across brain areas sampled, suggesting intranasal delivery may be scaled up to achieve desired target concentrations, if necessary. Intranasal application of smaller antibody fragments resulted in even higher brain levels when compared to full length antibody delivery, as expected. Work evaluating whether intranasal application of a novel, physiologic absorption enhancer produces higher brain levels of intranasally applied antibody fragments is ongoing.