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

Year: 2023

Authors: Pernet V., Joly S., Spiegel S., Meli I., Idriss S., Maigler F., Mdzomba JB., Roenneke AK., Franceschini A., Silvestri L., Pavone FS., Calamai M., Schindowski K., Chan A.

Autors Affiliation: Univ Bern, Bern Univ Hosp, Dept Neurol, Inselspital, Bern, Switzerland; Univ Bern, Bern Univ Hosp, Ctr Expt Neurol ZEN, Bern, Switzerland; Univ Laval, Ctr Rech CHU Quebec, Quebec City, PQ, Canada; Univ Laval, Fac Med, Dept Mol Med, Quebec City, PQ, Canada; Univ Bern, Bern Univ Hosp, Dept Ophthalmol, Inselspital, Bern, Switzerland; Biberach Univ Appl Sci, Inst Appl Biotechnol, Hubertus Liebrecht Str 35, Biberach, Germany; Univ Bern, Dept Biomed Res, Bern, Switzerland; Univ Bern, Grad Sch Cellular & Biomed Sci, Bern, Switzerland; Univ Florence, LENS European Lab Nonlinear Spect, Sesto, Italy; Natl Res Council CNR, Natl Inst Opt INO, Sesto Fiorentino, Italy.

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.

Journal/Review: CELL DEATH DISCOVERY

Volume: 9 (1)      Pages from: 290-1  to: 290-12

More Information: This study has been supported by the European Union under the European Framework Programme for Research and Innovation Horizon 2020 under grant agreements no. 721098 (N2B-patch) and no. 871124 (Laserlab-Europe), by the Advanced Light Microscopy Italian Node -Euro Bioimaging, by the Baden-Wurttemberg State Ministry of Science, Research and Arts (FcRn in N2B’), and by the German Federal Ministry for Economic Affairs and Energy (BMWi, ALIVE’).
KeyWords: Blood-brain-barrier; Multiple-sclerosis; Neurite Outgrowth; White-matter; Growth-factor; Lesions; Neurodegeneration; Remyelination; Marlin-1; Bypasses
DOI: 10.1038/s41420-023-01588-7

Citations: 4
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