Multiple sclerosis (MS) is a highly prevalent autoimmune disease of the central nervous system (CNS). Several immunosuppressive treatments are efficient at reducing the severity of symptoms of the relapsing-remitting and the progressive forms of MS. However, the accumulation of neuronal lesions resulting from repeated relapses cause irreversible neurological deficits, give the fact that CNS neurons have a poor ability to spontaneously repair.

In the CNS of mammals, Nogo-A is a well characterised inhibitor of injured neuron regeneration and plasticity (Pernet 2017; Kempf und Schwab 2013). To neutralise the effect of Nogo-A in animal models of CNS injuries/diseases, a monoclonal antibody directed against its bioactive domain delta20 has been developed (Barske, et al. 2002). This antibody named 11C7 has been shown to promote axonal regeneration after spinal cord injury and blunt clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of MS induced by immunizing C57BL/6 mice with recombinant myelin oligodendrocyte glycoprotein (MOG35-55) (Karnezis et al. 2004; Kucher et al. 2018). In this model, after 10-12 days animals develop motor symptoms beginning in the tail tip with progression to hind limbs weakness and paralysis. Although intravenous administrations of 11C7 block the rise of motor deficits during inflammatory phase of EAE, an increase of symptoms is observed in the chronic phase. The effects of 11C7 on EAE may thus be restricted to a narrow time-window during which inflammation opens the blood-brain barrier (BBB), whereas the closure of the BBB in the chronic phase prevents the passage of the antibody from the periphery to the CNS. In general, the BBB is considered as a major obstacle to the penetration of therapeutic antibodies targeting CNS antigens such as Nogo-A. (Engelhardt und Ransohoff 2012; Mizee und Vries 2013; Karnezis et al. 2004).

However, our recent results show that intranasal administration of 11C7 is an efficient method to bypass the BBB in EAE mice, allowing the penetration of 11C7 in the whole CNS, and by significantly reducing motor deficits and demyelination. The mechanisms of antibody uptake across the olfactory epithelium and its transport into the brain and spinal cord have to be elucidated to use the intranasal delivery pathway in the treatment of CNS diseases such as MS. Our Hypotheses are that the neonatal Fc-receptor (FcRn) is required for the transcytosis of 11C7 through the olfactory epithelium, that the olfactory pathway is the predominant route of 11C7 transport in the CNS as opposed to the trigeminal pathway and that cell penetrating peptides can be used to enhance the uptake of 11C7 in the olfactory mucosa and thus improve its therapeutic effects in EAE mice.