Fingolimod and Teriflunomide Attenuate Neurodegeneration in Mouse Models of Neuronal Ceroid Lipofuscinosis

Abstract

CLN diseases are rare lysosomal storage diseases characterized by progressive axonal degeneration and neuron loss in the CNS, manifesting in disability, blindness, and premature death. We have previously demonstrated that, in animal models of infantile and juvenile forms of CLN disease (CLN1 and CLN3, respectively), secondary neuroinflammation in the CNS substantially amplifies neural damage, opening the possibility that immunomodulatory treatment might improve disease outcome. First, we recapitulated the inflammatory phenotype, originally seen in mice in autopsies of CLN patients. We then treated mouse models of CLN1 and CLN3 disease with the clinically approved immunomodulatory compounds fingolimod (0.5 mg/kg/day) and teriflunomide (10 mg/kg/day) by consistent supply in the drinking water for 5 months. The treatment was well tolerated and reduced T cell numbers and microgliosis in the CNS of both models. Moreover, axonal damage, neuron loss, retinal thinning, and brain atrophy were substantially attenuated in both models, along with reduced frequency of myoclonic jerks in Ppt1−/− mice. Based on these findings, and because side effects were not detected, we suggest that clinically approved immune modulators such as fingolimod and teriflunomide may be suitable to attenuate progression of CLN1 and CLN3 disease and, possibly, other orphan diseases with pathogenically relevant neuroinflammation.

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

“…Interestingly, one mechanism how Sn expression on microglia/macrophages contributes to disease progression is the suppression of CD8 1 CD1221 regulatory T-cells. In a recent study, the immune modulators fingolimod and teriflunomide, both approved for multiple sclerosis, substantially attenuated neuroinflammation and improved disease outcome in CLN1 and CLN3 models, giving hope for future clinical interventions (Groh, Berve, & Martini, 2017). Additional microglia/macrophagerelated mechanisms are likely to contribute to the amplification of neural damage, as an increased expression of proinflammatory neurotoxic cytokines and oxidative damage have been reported in the mouse models (Benedict, Sommers, & Pearce, 2007;Groh et al, 2016b;Wei et al, 2008;Xiong & Kielian, 2013).…”

“…Treatment with the antineuroinflammatory, small molecule MW151 was shown to have some beneficial effects on disease characteristics in a CLN1 model (Macauley et al, 2014), whereas the immune suppressant CellCept/mycophenolate mofetil ameliorated some mild symptoms in young models of CLN3 disease (Seehafer et al, 2011). In a recent study, the immune modulators fingolimod and teriflunomide, both approved for multiple sclerosis, substantially attenuated neuroinflammation and improved disease outcome in CLN1 and CLN3 models, giving hope for future clinical interventions (Groh, Berve, & Martini, 2017).…”

“…While staging, extent and region-specificity appear to differ between the distinct subtypes, neuroinflammation has also been observed in models of CLN2, CLN5, and CLN6, indicating that it might act as a common modifier of disease outcome (Cooper et al, 2015;Geraets et al, 2016). Additionally, there are some observations indicating that neuroinflammation is a typical feature in CLN disease patients (Lim et al, 2007;Tyynela, Cooper, Khan, Shemilts, & Haltia, 2004;Groh et al, 2017). These combined observations clearly point to the urgent necessity for future preclinical treatment activities using modern and clinically approved immunomodulatory drugs to mitigate the devastating symptoms of the still untreatable disorders.…”

Teriflunomide Modulates Vascular Permeability and Microglial Activation after Experimental Traumatic Brain Injury

“…We found that, while the higher doses (3 and 10 mg/kg) significantly reduced neuroinflammation as indicated by the accumulation and activation of Iba-1+ cells, there was an inverse correlation between the doses tested and both blood-brain barrier permeability and neuroinflammation. These doses have been previously reported to be therapeutic to treat other rodent models of neurological conditions, [61][62][63] although those studies utilized different strains of rats and modeled neurodegenerative diseases rather than trauma. Future mechanistic studies are required to determine why the higher doses (3 and 10 mg/kg) did not attenuate the BBB breakdown in our model of TBI.…”

Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses

“…However, short-term administration of mycophenolate mofetil to patients with CLN3 disease did not show a clinical benefit [ 24 ]. A potential therapeutic benefit of the immunomodulatory compounds fingolimod and teriflunomide was demonstrated in mouse models of CLN1 and CLN3 disease [ 25 ]. Oral administration of fingolimod and teriflunomide reduced microgliosis, neuron loss, and brain atrophy in Ppt1 ko and Cln3 ko mice.…”