Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination

Katharina Robichon; Rabia Bibi; Mackenzie Kiernan; Lisa Denny; Thomas E Prisinzano; Bronwyn M Kivell; Anne Camille La Flamme

doi:10.1002/cti2.1480

Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination

Clin Transl Immunology. 2023 Dec 12;12(12):e1480. doi: 10.1002/cti2.1480. eCollection 2023.

Authors

Katharina Robichon^{1

2}, Rabia Bibi^{1

2}, Mackenzie Kiernan^{1

2}, Lisa Denny^{1

2}, Thomas E Prisinzano³, Bronwyn M Kivell^{1

2}, Anne Camille La Flamme^{1

2

4}

Affiliations

¹ School of Biological Sciences Victoria University of Wellington Wellington New Zealand.
² Centre for Biodiscovery Wellington Victoria University of Wellington Wellington New Zealand.
³ Department of Medicinal Chemistry University of Kentucky Lawrence KY USA.
⁴ Malaghan Institute of Medical Research Wellington New Zealand.

Abstract

Objectives: Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease-modifying treatments (DMTs) are very effective at reducing relapses, they do not slow the progression of the disease, and there is little evidence that these treatments are able to repair or remyelinate damaged axons. Recent evidence suggests that activating kappa opioid receptors (KORs) has a beneficial effect on the progression of MS, and this study investigates the effects of KOR agonists treatment in combination with two current DMTs.

Methods: Using the well-established murine model for immune-driven demyelination of MS, experimental autoimmune encephalomyelitis, the effect of KOR agonists in combination with DMTs fingolimod or dimethyl fumarate on disease progression, immune cell infiltration and activation as well as myelination were analysed.

Results: Fingolimod in combination with the KOR agonist, nalfurafine, significantly increased each individual beneficial effect as measured by increased recovery of mice and reduced relapses. These beneficial effects correlated with a reduction in immune cell infiltration into the CNS as well as peripheral immune cell alterations including a reduction in autoreactive CD4⁺ T-cell cytokine production as well as increased myelination in the spinal cords of co-treated animals. In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits.

Conclusion: This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine-fingolimod combination providing enhanced benefits.

Keywords: experimental autoimmune encephalomyelitis; fingolimod; kappa opioid receptor agonist; nalfurafine; neuroinflammation; remyelination.