Nasal Delivery of Interferon-beta at Lower Doses Shows MS Treatment Potential in Mice

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by Steve Bryson PhD |

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Nasal delivery of Rebif’s active ingredient interferon-beta, loaded in carbohydrate-based nanoparticles, reduced disease progression and nerve cell inflammation in a preclinical mouse model of multiple sclerosis (MS), a study demonstrated.

This alternate, non-invasive, low-cost treatment strategy has the potential to bypass the limitations of under-the-skin (subcutaneous) injections of Rebif and reduce the effective dose needed to achieve efficacy, the researchers said. 

The study, “Intranasal delivery of interferon-β-loaded nanoparticles induces control of neuroinflammation in a preclinical model of multiple sclerosis: A promising simple, effective, non-invasive, and low-cost therapy,” was published in the Journal of Controlled Release.

Rebif, marketed by EMD Serono (known as Merck KGaA outside the U.S. and Canada), is an approved, first-line MS therapy that reduces inflammation in nerve cells (neurons) in the brain and spinal cord. It suppresses attacks on the myelin sheath, the protective coating surrounding neurons, easing disease symptoms.

However, many MS patients are unresponsive to Rebif or discontinue treatment due to adverse effects. Reduced efficacy is thought to be caused by its quick elimination from the body (short half-life) and limited access to the central nervous system (CNS), comprised of the brain and spinal cord, which is the therapy’s target tissue. 

Regular infusions also can trigger injection-site reactions, including rash, swelling, and skin stiffness. Such side effects can cause discomfort, leading to poor adherence, treatment failure, and ultimately, to a worse long-term prognosis for MS patients. Further, continuous systemic exposure of high doses of the medication can prompt an immune response against the therapy, reducing its effectiveness. 

Rebif’s direct delivery via the nasal cavity — intranasal, or through the nose — is a promising strategy to reach the CNS with less systemic side effects and more local control over inflammation. Moreover, this method is non-invasive and relatively easy to use. 

Studies in healthy rats and non-human primates have shown that interferon-beta reaches the CNS following intranasal administration. However, the absorption of therapies applied through the nose is limited due to mucus clearance processes that decrease the therapy’s permanence time — how long it lasts — in the nasal cavity.

To address this problem, a team led by researchers at the University of Chile designed a new carbohydrate-based nanoparticle (NP) nasal delivery system, loaded with interferon-beta, and tested it in mouse models of MS. 

The nanoparticles — submicroscopic in size and undetectable by the human eye — were composed of chitosan, a non-toxic, biocompatible polysaccharide that has been used for treatment delivery, and sulfobutylether-cyclodextrin (SBE-CD), a circular carbohydrate approved by the U.S. Food and Drug Administration for several pharmaceutical applications, including some nasal formulations. 

Initial cell-based tests showed the nanoparticles with interferon-beta (IFN-beta-NP) had no effect on cell viability, and thus were non-toxic. The nanoparticles allowed for the slow and sustained release of interferon-beta that retained its biological activity, these tests showed.

Healthy mice were then administered nanoparticles, or NPs, in the nasal cavity loaded with a fluorescent probe. There was an early and high fluorescence signal in the brain, demonstrating the nanoparticles’ ability to deliver molecules to the target tissue.

Experimental autoimmune encephalomyelitis (EAE)-induced mice, a common MS mouse model, were treated daily with nasal-administered IFN-beta-NPs after clinical symptoms of the disease were observed. 

Compared with control treatment (NPs without IFN-beta), mice treated with a high dose of IFN-beta-NPs showed significant and sustained disease suppression, although the beneficial effect was not maintained over time. In contrast, injecting free IFN-beta without nanoparticles, intranasally or into the abdomen of EAE mice, had no effect on disease progression.

Lower doses of IFN-beta-NPs, given at different frequencies, were equally effective at reducing clinical symptoms compared with the high dose. The treatment demonstrated significant efficacy even with 50% less IFN-beta and when administered 33% less often, which meant “a reduction in the total amount of weekly administered [IFN-beta] of 78% compared to daily treatment with nasal [IFN-beta-NPs],” the researchers wrote. 

An examination of spinal cords isolated from treated EAE mice showed fewer inflamed cells and demyelinated nerve fibers, compared with the extensive tissue damage and demyelination seen in untreated mice or those given free IFN-beta via the abdomen. 

Control EAE mice had significantly more activation of two brain cell types related to demyelination, known as astrocytes and microglia. In contrast, EAE mice treated with IFN-beta-NPs showed significantly lower activation of these cells, as well as reduced production of immune cell proteins that stimulate an immune response. 

“These findings might represent a substantial improvement for the current MS therapy based on free [IFN-beta] or other immunomodulatory drugs administered by systemic routes,” the researchers wrote.

“Moreover, encapsulation of [IFN-beta] and its intranasal administration allowed a significant reduction of the effective dose of the [therapy], which combined with relatively inexpensive nanoparticle components, represent a potential low-cost treatment for MS,” the team added. 

The researchers concluded that IFN-beta-NPs “represent an innovative and promising therapeutic development.”

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