The intranasal route has been hypothesized to circumvent the blood-brain and blood-cerebrospinal fluid barriers, allowing entry into the brain via extracellular pathways along olfactory and trigeminal nerves and the perivascular spaces (PVS) of cerebral blood vessels. We investigated the potential of the intranasal route to non-invasively deliver antibodies to the brain 30 min following administration by characterizing distribution, dose-response, and mechanisms of antibody transport to and within the brain after administering non-targeted radiolabeled or fluorescently-labeled full length immunoglobulin G (IgG) to normal adult female rats. Intranasal [I]-IgG consistently yielded highest concentrations in the olfactory bulbs, trigeminal nerves, and leptomeningeal blood vessels with their associated PVS. Intranasal delivery also resulted in significantly higher [I]-IgG concentrations in the CNS than systemic (intra-arterial) delivery for doses producing similar endpoint blood concentrations. Importantly, CNS targeting significantly increased with increasing dose only with intranasal administration, yielding brain concentrations that ranged from the low-to-mid picomolar range with tracer dosing (50 μg) up to the low nanomolar range at higher doses (1 mg and 2.5 mg). Finally, intranasal pre-treatment with a previously identified nasal permeation enhancer, matrix metalloproteinase-9, significantly improved intranasal [I]-IgG delivery to multiple brain regions and further allowed us to elucidate IgG transport pathways extending from the nasal epithelia into the brain using fluorescence microscopy. The results show that it may be feasible to achieve therapeutic levels of IgG in the CNS, particularly at higher intranasal doses, and clarify the likely cranial nerve and perivascular distribution pathways taken by antibodies to reach the brain from the nasal mucosae.

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Passive immunotherapy, i.e., the administration of exogenous antibodies that recognize a specific target antigen, has gained significant momentum as a potential treatment strategy for several central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain cancer, among others. Advances in antibody engineering to create therapeutic antibody fragments or antibody conjugates have introduced new strategies that may also be applied to treat CNS disorders. However, drug delivery to the CNS for antibodies and other macromolecules has thus far proven challenging, due in large part to the blood-brain barrier and blood-cerebrospinal fluid barriers that greatly restrict transport of peripherally administered molecules from the systemic circulation into the CNS. Here, we summarize the various passive immunotherapy approaches under study for the treatment of CNS disorders, with a primary focus on disease-specific and target site-specific challenges to drug delivery and new, cutting edge methods.

Objective: The goal of the study was to identify the potential nutrigenetic effects to inulin, a prebiotic fiber, in mice with different human apolipoprotein E (APOE) genetic variants. Specifically, we compared responses to inulin for the potential modulation of the systemic metabolism and neuroprotection via gut-brain axis in mice with human APOE ε3 and ε4 alleles. Method: We performed experiments with young mice expressing the human APOE3 (E3FAD mice and APOE4 gene (E4FAD mice). We fed mice with either inulin or control diet for 16 weeks starting from 3 months of age. We determined gut microbiome diversity and composition using16s rRNA sequencing, systemic metabolism using in vivo MRI and metabolomics, and blood-brain barrier (BBB) tight junction expression using Western blot. Results: In both E3FAD and E4FAD mice, inulin altered the alpha and beta diversity of the gut microbiome, increased beneficial taxa of bacteria and elevated cecal short chain fatty acid and hippocampal scyllo-inositol. E3FAD mice had altered metabolism related to tryptophan and tyrosine, while E4FAD mice had changes in the tricarboxylic acid cycle, pentose phosphate pathway, and bile acids. Differences were found in levels of brain metabolites related to oxidative stress, and levels of Claudin-1 and Claudin-5 BBB tight junction expression. Discussion: We found that inulin had many similar beneficial effects in the gut and brain for both E3FAD and E4FAD mice, which may be protective for brain functions and reduce risk for neurodegeneration. . E3FAD and E4FAD mice also had distinct responses in several metabolic pathways, suggesting an APOE-dependent nutrigenetic effects in modulating systemic metabolism and neuroprotection.

Passive immunotherapy has become a prominent therapeutic strategy for the treatment of many different neurological disorders. Antibodies can be targeted to the pathogenic proteins of diseases such as Alzheimer's (e.g., beta‐amyloid and phosphorylated tau), Parkinson's (e.g., alpha‐synuclein), and multiple sclerosis (e.g., CD20 marker on B cells). However, delivery of antibodies to the central nervous system (CNS) following systemic administration is significantly impeded as a result of the blood‐brain barrier (BBB) and blood‐cerebrospinal‐fluid barriers (BCSFBs). The intranasal route has been hypothesized to circumvent the BBB and BCSFBs and allow entry into the brain via extracellular pathways along cranial nerves and the perivascular spaces (PVS) of cerebral blood vessels (Thorne et al. Neuroscience 2004 & 2008; Lochhead et al. J. Cereb. Blood Flow & Metab. 2015). Here, we demonstrate the potential of intranasal delivery as a non‐invasive strategy to bypass the BBB and BCSFBs to rapidly target full length immunoglobulin G (IgG) antibodies to the CNS. Quantitative distribution studies of radiolabeled IgG in the CNS of anesthetized rats revealed that intranasal delivery achieved significantly higher antibody levels in both the CNS and CSF compared to systemic delivery at doses resulting in matched blood exposure via either route. Additional experiments exploring the intactness of radiolabeled IgG in the brain following intranasal delivery were conducted to identify the biochemical conditions necessary for IgG intactness in vivo. Finally, by utilizing fluorophore‐labeled IgG, we provide direct evidence of intranasal IgG transport along perineural and perivascular pathways that directly connect the nasal mucosa to CNS target sites. Our results suggest olfactory and trigeminal nerve‐associated perineural channels provide direct pathways to the olfactory bulbs and brainstem, respectively. Once within the brain, further distribution along perivascular spaces of cerebral blood vessels is capable of transporting IgG to widespread regions of the brain. Our findings highlight that the intranasal route can provide a non‐invasive, direct, and rapid method for targeting antibodies to the CNS, bypassing the BBB and BCSFBs in a way that merits further consideration for the treatment of neurological diseases.Support or Funding InformationSupported by the University of Wisconsin‐Madison School of Pharmacy, the Graduate School at the University of Wisconsin, the Michael J. Fox Foundation for Parkinson's Research, the Parkinson's Foundation, the Wisconsin Alzheimer's Disease Research Center (NIH P50‐AG033514), the Wisconsin institute for Clinical and Translational Research (Clinical and Translational Science Award program through the NIH National Center for Advancing Translational Sciences, grant UL1TR000427), and the Wisconsin Alumni Research Foundation grant 135 PRJ82AZ.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.