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Efficacy and tolerability of a folic acid derivative of aminopterin in a rat focal model of multiple sclerosis

Elo, Petri and Li, Xiang-Guo and Liljenbäck, Heidi and Gardberg, Maria and Moisio, Olli and Miner, Maxwell and Virta, Jenni and Saraste, Antti and Srinivasarao, Madduri and Pugh, Michael and Low, Philip and Knuuti, Juhani and Jalkanen, Sirpa and Airas, Laura and Lu, June and Roivainen, Anne (2021) Efficacy and tolerability of a folic acid derivative of aminopterin in a rat focal model of multiple sclerosis. J Neuroinflammation, 18 (30).

Abstract

Background: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of 68 Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS. Methods: Focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). 68Ga-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-β expression in postmortem brain samples from 5 patients with MS and 5 healthy controls. Results: Immunofluorescence and histological analyses revealed significant reductions in FR-β expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-β positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples. Conclusions: EC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-β-positive cells in chronically active plaques, which suggests that these results may have translational relevance.

Item Type: Article
Keywords: Aminopterin, Folate receptor, Experimental autoimmune encephalomyelitis, Inflammation, Macrophages, Multiple sclerosis, Positron emission tomography
Date Deposited: 09 Feb 2021 00:45
Last Modified: 09 Feb 2021 00:45
URI: https://oak.novartis.com/id/eprint/43001

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