Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells

Abstract

Huntington's disease (HD) is a neurodegenerative condition characterized by pathology in the brain and peripheral tissues. Hyperactivity of the innate immune system, due in part to NFjB pathway dysregulation, is an early and active component of HD. Evidence suggests targeting immune disruption may slow disease progression. Laquinimod is an orally active immunomodulator that down-regulates proinflammatory cytokine production in peripheral blood mononuclear cells, and in the brain down-regulates astrocytic and microglial activation by modulating NFjB signalling. Laquinimod had beneficial effects on inflammation, brain atrophy and disease progression in multiple sclerosis (MS) in two phase III clinical trials. This study investigated the effects of laquinimod on hyperactive proinflammatory cytokine release and NFjB signalling in HD patient myeloid cell cultures. Monocytes from manifest (manHD) and pre-manifest (preHD) HD gene carriers and healthy volunteers (HV) were treated with laquinimod and stimulated with lipopolysaccharide. After 24 h pre-treatment with 5 lM laquinimod, manHD monocytes released lower levels of IL-1b, IL-5, IL-8, IL-10, IL-13 and TNFa in response to stimulation. PreHD monocytes released lower levels of IL-8, IL-10 and IL-13, with no reduction observed in HV monocytes. The effects of laquinimod on dysfunctional NFjB signalling in HD was assessed by inhibitor of kappa B (IjB) degradation kinetics, nuclear translocation of NFjB and interactions between IjB kinase (IKK) and HTT, in HD myeloid cells. No differences were observed between laquinimod-treated and untreated conditions. These results provide evidence that laquinimod dampens hyper-reactive cytokine release from manHD and preHD monocytes, with a much reduced effect on HV monocytes.

Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease

“…While this paper was under review, a study was published in which the effect of laquinimod on myeloid cells of patients with HD was evaluated ex vivo 53 . Monocytes of premanifest and manifest HD gene carriers that were pre-treated with laquinimod for 24 hr ex vivo released lower levels of inflammatory factors following stimulation compared with monocytes of healthy volunteers 53 , supporting a dampening effect of laquinimod on the hyperactive inflammatory myeloid response in HD.…”

Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

“…Laquinimod was able to dampen hyperreactive production of cytokines from monocytes exposed to LPS harvested from both premanifest and symptomatic HD mutant human carriers [59]. A clinical trial is currently recruiting patients with HD in order to investigate the safety and efficacy of laquinimod (NCT02215616, Table 1).…”

Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington's disease

“…Indeed, current anti‐inflammatory therapies have been tested in animal models and in patients with HD, such as XPro595, an inhibitor of TNF‐α and Laquinimod (NCT02215616), an immunomodulator of activated monocytes . Although not belonging to the classical definition of anti‐inflammatory drugs, minocycline and cannabinoids have also been tested in HD and have been shown to possess anti‐inflammatory properties in preclinical studies and clinical trials .…”

“…Indeed, current anti-inflammatory therapies have been tested in animal models and in patients with HD, 6 such as XPro595, an inhibitor of TNF-α 7 and Laquinimod (NCT02215616), an immunomodulator of activated monocytes. 8 Although not belonging to the classical definition of anti-inflammatory drugs, minocycline and cannabinoids have also been tested in HD and have been shown to possess antiinflammatory properties in preclinical studies and clinical trials. [9][10][11] However, the protective effects of minocycline are controversial, despite the fact that minocycline has been reported to be well tolerated and safe, 10 a worsening of the disease along with detrimental effects, have been reported in animal models 12,13 and HD patients.…”