Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS

Vincent Pernet; Sandrine Joly; Sebastian Spiegel; Ivo Meli; Sherif Idriss; Frank Maigler; Julius Baya Mdzomba; Anna K Roenneke; Alessandra Franceschini; Ludovico Silvestri; Francesco S Pavone; Martino Calamai; Katharina Schindowski; Andrew Chan

doi:10.1038/s41420-023-01588-7

Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS

Cell Death Discov. 2023 Aug 9;9(1):290. doi: 10.1038/s41420-023-01588-7.

Authors

Vincent Pernet^{1

2

3}, Sandrine Joly^{4

5

6}, Sebastian Spiegel^{4

5

7

8

9}, Ivo Meli^{4

5}, Sherif Idriss^{4

5}, Frank Maigler⁷, Julius Baya Mdzomba^{4

5}, Anna K Roenneke^{4

5}, Alessandra Franceschini¹⁰, Ludovico Silvestri¹⁰, Francesco S Pavone¹⁰, Martino Calamai^{10

11}, Katharina Schindowski⁷, Andrew Chan^{12

13

14}

Affiliations

¹ Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. vincent.pernet@insel.ch.
² Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Bern, Switzerland. vincent.pernet@insel.ch.
³ Centre de recherche du CHU de Québec-Université Laval and Department of Molecular Medicine, Faculté de médecine, Université Laval, Québec, Québec, Canada. vincent.pernet@insel.ch.
⁴ Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁵ Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Bern, Switzerland.
⁶ Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁷ Institute of Applied Biotechnology, Biberach University of Applied Science, Hubertus-Liebrecht-Strasse 35, Biberach, Germany.
⁸ Department of Biomedical Research, University of Bern, Bern, Switzerland.
⁹ Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
¹⁰ LENS- European Laboratory for Non-Linear Spectroscopy, University of Florence, Sesto-Fiorentino (Firenze), Italy.
¹¹ National Institute of Optics - National Research Council (CNR-INO), Sesto Fiorentino, Italy.
¹² Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. andrew.chan@insel.ch.
¹³ Center for experimental neurology (ZEN), Bern University Hospital, University of Bern, Bern, Switzerland. andrew.chan@insel.ch.
¹⁴ Department of Biomedical Research, University of Bern, Bern, Switzerland. andrew.chan@insel.ch.

Abstract

Systemic administration of Nogo-A-neutralizing antibody ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the blood-brain barrier (BBB) is a major obstacle limiting the passage of systemically applied antibody to the CNS. To bypass the BBB, in the present study we tested the intranasal route of administration by targeting the olfactory mucosa with the Nogo-A-blocking antibody 11C7 mAb in myelin oligodendrocyte glycoprotein-induced EAE. Antibodies were specifically administered onto the olfactory mucosa using a microcatheter. Antibody distribution was examined in the CNS by ELISA and light-sheet microscopy. The effects of 11C7 mAb on Nogo-A signaling were assessed by Western blotting. EAE-induced deficits were monitored daily. Demyelination was observed on spinal cord histological sections. Gene expression changes were followed by trancriptomic analyses. A sensitive capture ELISA revealed a rapid and widespread distribution of 11C7 mAb in the CNS, including the olfactory bulb, the cerebellum and the lumbar spinal cord, but not in the CSF. Light-sheet microscopy allowed to observe antibody accumulation in the parenchyma, thus demonstrating nose-to-brain transfer of IgG. At the functional level, the widespread penetration of 11C7 mAb in the CNS, including the thoracolumbar spinal cord, resulted in the improvement of motor symptoms and in the preservation of myelin in the spinal cord of EAE mice. This was accompanied by Nogo-A signaling downregulation, as reflected by the decreased level of phosphorylated cofilin observed by Western blotting in the cerebellum. In the brain of EAE score-matched animals, 11C7 modified the expression of genes that can influence neurotransmission and cognitive functions, independently of the demyelination phenotype in the spinal cord. In conclusion, our data show the feasibility of olfactory mucosa-directed administration for the delivery of therapeutic antibodies targeting CNS antigens in EAE mice.