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bioRxiv · 10.1101/2023.01.22.524916

Supporting central nervous system neuroprotection and remyelination by specific TLR4 antagonism

Fernandez-Gomez, B.·Marchena, M. A.·Pineiro, D.·Lao, Y.·Valencia, G.·Nocera, S.·Benitez-Fernandez, R.·Gomez-Martin, P.·Castano-Leon, A. M.·Lagares, A.·Hernandez-Jimenez, M.·de Castro, F.
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Abstract

ApTOLL is an aptamer specifically designed to antagonize Toll-Like Receptor 4 (TLR4), a relevant actor for innate immunity involved in inflammatory responses in multiple sclerosis (MS) and other diseases. MS is a primary demyelinating, chronic, inmune and neurodegenerative disease of the central nervous system that normally debuts in young adults. The currently available therapeutic arsenal to treat MS is composed of immunomodulators but, to date, there are no (re)myelinating drugs available in clinics. Our present study shows cells expressing TLR4 in demyelinating lesions of MS patients (postmortem samples from cerebral cortex) and, as a derivative, we studied the effect of TLR4 inhibition with ApTOLL in animal models of MS (experimental autoimmune encephalomyelitis -EAE- and the cuprizone). The treatment with ApTOLL positively impacted the clinical symptomatology, and this was associated with better preservation plus restoration of myelin and oligodendrocytes in the demyelinated lesions of these animals, which suggests not only an immunomodulatory but also a remyelinating effect of the treatment with ApTOLL. This latter was corroborated on purified cultures of rodent and adult human oligodendrocyte precursor cells (OPCs), confirming the expression of TLR4 in this cell type. Altogether, the molecular nature of ApTOLL and its mechanism/s of action strongly supports this compound as a novel candidate to treat MS and other demyelinating scenarios.

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Fernandez-Gomez, B., Marchena, M. A., Pineiro, D., Lao, Y., Valencia, G., Nocera, S., Benitez-Fernandez, R., Gomez-Martin, P., Castano-Leon, A. M., Lagares, A., Hernandez-Jimenez, M., de Castro, F.. 2023-01-22. Supporting central nervous system neuroprotection and remyelination by specific TLR4 antagonism. https://doi.org/10.1101/2023.01.22.524916

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