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Fingolimod Rescues Demyelination in a Mouse Model of Krabbe's Disease

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Fingolimod Rescues Demyelination in a Mouse Model of Krabbe's Disease Research Articles: Neurobiology of Disease Fingolimod rescues demyelination in a mouse model of Krabbe's disease https://doi.org/10.1523/JNEUROSCI.2346-19.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2346-19.2020 Received: 30 September 2019 Revised: 17 December 2019 Accepted: 21 January 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 Be´chet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Fingolimod rescues demyelination in a mouse model of Krabbe’s disease 2 Sibylle Béchet, Sinead O’Sullivan, Justin Yssel, Steven G. Fagan, Kumlesh K. Dev 3 Drug Development, School of Medicine, Trinity College Dublin, IRELAND 4 5 Corresponding author: Prof. Kumlesh K. Dev 6 Corresponding author’s address: Drug Development, School of Medicine, Trinity College 7 Dublin, IRELAND, D02 R590 8 Corresponding author’s phone and fax: Tel: +353 1 896 4180 9 Corresponding author’s e-mail address: [email protected] 10 11 Number of pages: 35 pages 12 Number of figures: 9 figures 13 Number of words (Abstract): 216 words 14 Number of words (Introduction): 641 words 15 Number of words (Discussion): 1475 words 16 17 Abbreviated title: Investigating the use of FTY720 in Krabbe’s disease 18 19 Acknowledgement statement (including conflict of interest and funding sources): This work 20 was supported, in part, by Trinity College Dublin, Ireland and the Health Research Board, 21 Ireland. S.B. is a Ph.D scholar of Trinity College Dublin. We would like to thank Dr. Catherine 22 O’Sullivan (Trinity College Dublin) for aiding in the earlier parts of this study. The authors 23 declare no competing financial interests. 24 Abstract 25 Krabbe’s disease is an infantile neurodegenerative disease, affected by mutations in the 26 lysosomal enzyme galactocerebrosidase, leading to the accumulation of its metabolite 27 psychosine. We have shown previously that the S1P receptor agonist fingolimod (FTY720) 28 attenuates psychosine-induced glial cell death and demyelination both in vitro and ex vivo 29 models. This data, together with a lack of therapies for Krabbe’s disease, prompted the current 30 preclinical study examining the effects of fingolimod in twitcher mice, a murine model of 31 Krabbe’s disease. Twitcher mice, both male and female, carrying a natural mutation in the 32 GALC gene were given fingolimod via drinking water (1mg/kg/day). The direct impact of 33 fingolimod administration was assessed via histochemical and biochemical analysis using 34 markers of myelin, astrocytes, microglia, neurons, globoid and immune cells. The effects of 35 fingolimod on twitching behaviour and lifespan was also demonstrated. Our results show that 36 treatment of twitcher mice with fingolimod significantly rescued myelin levels compared to 37 vehicle treated animals and also regulated astrocyte and microglial reactivity. Furthermore, 38 non-phosphorylated neurofilament levels were decreased indicating neuroprotective and 39 neurorestorative processes. These protective effects of fingolimod on twitcher mice brain 40 pathology, was reflected by an increased lifespan of fingolimod treated twitcher mice. These 41 in vivo findings corroborate initial in vitro studies and highlight the potential use of S1P 42 receptors as drug targets for Krabbe’s disease. 43 44 Keywords: Globoid cell leukodystrophy; Krabbe’s disease; FTY720; Fingolimod; myelination, 45 neurodevelopmental disease 2 | Page 46 Significance Statement 47 This study demonstrates that administration of the therapy, known as fingolimod, in a mouse 48 model of Krabbe’s disease (namely, the twitcher mouse model) significantly rescues myelin 49 levels. Further, this drug fingolimod, also regulates the reactivity of glial cells, astrocyte and 50 microglia, in this mouse model. These protective effects of fingolimod result in an increased 51 lifespan of twitcher mice. 52 53 3 | Page 54 Introduction 55 Krabbe’s disease (globoid cell leukodystrophy) is a devastating illness that is invariably fatal 56 within the first two years of life (Graziano and Cardile 2015). This disease has orphan status 57 affecting approximately 1:100,000 births, although the incidence varies in different 58 populations (Barczykowski et al. 2012). Krabbe’s disease is an inherited lipid storage disorder 59 resulting from oligodendrocyte cell death and subsequent loss of myelin. The disease is caused 60 by mutations in the galc gene encoding for galactosylceramidase (GALC) (Suzuki and Suzuki 61 1970). Mutations in GALC result in enzymatic dysfunction and a build-up of its two metabolites 62 galactosylceramide and the toxic galactolipid galactosylsphingosine (psychosine) (Suzuki 63 1998). Aggregations of the latter is particularly apparent in the white matter of the brain and 64 in sciatic nerves, where it has been shown to inhibit some critical cell processes resulting in 65 oligodendrocyte and Schwann cell apoptosis (Giri et al. 2008, Misslin et al. 2017). Pathological 66 features of Krabbe’s disease therefore include profound demyelination and almost complete 67 loss of oligodendrocytes in the white matter, accompanied by inflammatory mechanisms 68 including reactive astrocytosis and infiltration of numerous multinucleated phagocytes termed 69 ‘globoid cells’ (Suzuki 2003). 70 71 The clinical phenotype of Krabbe’s disease is classified based on the age of disease onset, with 72 the majority of cases affecting infants (Wenger et al. 2016). Infantile Krabbe’s disease typically 73 develops within the first six months postnatal with progressive rapid neurologic deterioration. 74 Hallmark symptoms of the classic infantile forms include irritability, hypertonic spasticity and 75 psychomotor stagnation, followed by rapid developmental decline, seizures and optic atrophy 76 (Graziano and Cardile 2015). Clinical manifestations thus suggest involvement of both the first 4 | Page 77 and second motor neurons, indicative of a systemic disorder affecting the central as well as 78 the peripheral nervous systems. To date there is no therapeutic cure for Krabbe’s disease. A 79 number of therapeutic strategies have been described, targeting various levels of the 80 pathomechanistic cascade in order to lower the psychosine load and reduce its neural toxicity 81 (Bongarzone et al. 2016). The current standard of care for patients with Krabbe’s disease is 82 limited to hematopoietic stem cell transplantations, derived from bone marrow or umbilical 83 cord blood (Escolar et al. 2005). While this treatment has been shown to slow disease 84 progression, it fails to correct peripheral neuropathy in infants (Escolar et al. 2005, Duffner et 85 al. 2009). With increasing evidence suggesting Krabbe’s disease to be a multi-modal illness, 86 which includes ongoing inflammatory and neuronal pathologies, a combination of therapies 87 targeting these processes may prove more promising. 88 89 Previously, we have shown that psychosine causes human and mouse astrocyte toxicity in 90 culture and demyelination in mouse organotypic slice cultures, effects which were attenuated 91 by sphingosine 1-phosphate receptor (S1PR) agonists fingolimod and siponimod (O'Sullivan 92 and Dev 2015, O'Sullivan et al. 2016). S1PRs are G-protein coupled and expressed in many cell 93 types including immune, cardiovascular and central nervous systems (Dev et al. 2008). The 94 drug fingolimod targets all five S1PR subtypes, apart from S1PR2 and is marketed as the first 95 oral therapy for relapsing-remitting multiple sclerosis (Kappos et al. 2015). Fingolimod is 96 described to work by internalising S1PRs in T-cells, thus limiting their egress from lymph nodes 97 and dampening inflammation in multiple sclerosis (Dev et al. 2008). Furthermore, it has been 98 extensively demonstrated that S1PRs regulate neuronal and glial cell function. Briefly, in glial 99 cells, S1PRs play a role in oligodendrocyte differentiation, survival and myelination state, 100 astrocyte cell migration, survival and cell signalling, and microglia reactivity and pro- 5 | Page 101 inflammatory cytokine release (Miron et al. 2008, Miron et al. 2010, Sheridan and Dev 2014, 102 O'Sullivan and Dev 2015, O'Sullivan et al. 2016). 103 104 Given fingolimod may have potential to alter both inflammatory and neuronal dysfunction in 105 both the brain and periphery, and having previously shown that S1PR agonists attenuate 106 psychosine-induced cell death of astrocytes and demyelination in vitro, the current study 107 aimed to examine in vivo effects of fingolimod in twitcher mice, the murine model of Krabbe’s 108 disease. 6 | Page 109 Materials and Methods 110 Animals and experimental design 111 A breeding colony of heterozygous twitcher mice was established in a pathogen free 112 environment in the Comparative Medicine Unit Trinity College Dublin using mice obtained from 113 the Jackson Laboratory and maintained on a C57BL/6j genetic background (C57BL/6J-twi with 114 C57BL/6J-twi). Homozygous and heterozygous animals were identified using genotyping. 115 Heterozygous animals were only used for breeding
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