Benefits of intranasal Nogo-A antibody observed in mouse model

Delivering an antibody against the Nogo-A protein to a specific region of the nose called the olfactory mucosa improved motor function and preserved myelin in the spinal cord of a mouse model of multiple sclerosis (MS), according to a recent study.

This intranasal mode of delivery enabled significant concentrations of the antibody to reach the brain and spinal cord, collectively known as the central nervous system (CNS), which researchers believe underlies the observed benefits.

Scientists note the data offer “proof-of-concept” that an intranasal strategy targeting the olfactory mucosa — the mucus-secreting membrane in the upper part of the nose responsible for the sense of smell — could help to maximize the benefits not only of Nogo-A-targeted therapies for MS, but also other antibody-based treatments for CNS diseases.

The study, “Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS,” was published in Cell Death Discovery.

MS is marked by autoimmune attacks that lead to the progressive loss of myelin, the substance that surrounds and protects nerve cells. Therapies to stimulate myelin repair (remyelination) — potentially stopping or reversing neurological damage — are thus of significant interest for treating MS.

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Nogo-A protein involved in restricting nerve cell growth and myelination

Nogo-A is a protein that’s involved in restricting nerve cell growth and myelination, and is thus thought to be a promising target for increasing remyelination in neurodegenerative diseases.

Indeed, an antibody to neutralize the effects of Nogo-A, delivered directly into the bloodstream, was shown to reduce disease severity in a mouse model of MS.

However, it may be difficult to achieve sustained levels of the therapy in the CNS with systemic delivery, thus limiting the long-term effects of such a treatment, according to the researchers.

This is a common issue with treatments for neurological diseases. The blood-brain barrier (BBB), a highly selective membrane designed to protect the brain, prevents many molecules from passing from systemic circulation to the CNS, which precludes many therapeutics from reaching their target.

An intranasal route of delivery could help to circumvent that limitation. When inhaled through the nose, a treatment can bypass the BBB, allowing more of it to reach the brain. This approach is also less invasive than injections directly into the spinal canal.

As such, the scientists evaluated an intranasal route of administration for a Nogo-A antibody in mice. The antibody was delivered directly onto the cells lining the nose through a tiny catheter, or tube.

This intranasal delivery resulted in widespread accumulation of the antibody throughout the CNS in healthy mice and a mouse model of MS, which could be observed in some areas as early as 30 minutes after the treatment was given.

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Treatment led to improvements in motor function and myelin preservation

When given daily for a month to the MS mouse model, the antibody treatment did not influence the onset of symptoms, but did lead to improvements in motor function and myelin preservation in the spinal cord during chronic disease stages.

That’s in contrast to previous studies where Nogo-A antibodies were delivered into the bloodstream (intravenous). There, the treatment delayed symptom onset, but the effects were not long-lasting, according to the team.

“It is tempting to propose that a combined strategy using both intravenous and intranasal therapeutic delivery routes may be optimal for rapid and sustained therapeutic effects in the acute and chronic phases,” the researchers wrote.

The treatment was also linked to a small number of gene activity changes, particularly in genes associated with nerve cell signaling in the brain.

Nogo-A signaling was reduced with the treatment, consistent with its expected mechanism.

Taken together, the scientists believe the intranasal route of delivery “may offer the possibility to maintain the therapeutic effects of Nogo-A-targeting antibody in multiple sclerosis.”