Miglustat Improves Purkinje Cell Survival and Alters Microglial Phenotype in Feline Niemann-Pick Disease Type C

Abstract

Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 ± 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 ± 0.6 hours, 20.3 ± 4.6 μg/ml, and 104.1 ± 16.6 μg hours/ml, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats, and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains of treated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats.

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…150 ). In the feline model of NPC disease, miglustat decreased GM2 ganglioside accumulation and slightly delayed development of neurological symptoms ( 151 ). Similarly, in Npc1 Ϫ / Ϫ mice, miglustat reduced ganglioside storage in LEs/Ls.…”

Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling

“…Alternatively, miglustat may exert its effects through nonlipid storage or downstream pathways, or by enhancing neuronal survival through other mechanisms. Indeed, a recent study examining the effi cacy of miglustat in the feline NPC1 model revealed dramatic rescue of Purkinje neurons despite only modest effects on sphingolipid storage ( 26 ). Nonetheless, treatment of NPC1 patients with the sphingolipid synthesis inhibitor was associated with signifi cant reductions (LacCer and GM1 and GM3 gangliosides) and elevations (MC) in multiple circulating sphingolipid species.…”

“…The clinical, neuropathological, and biochemical abnormalities present in juvenile-onset patients are similarly faithfully modeled in a naturally-occurring feline model of NPC disease, which has a missense mutation in the Npc1 gene ( 19,20 ). Intervention with miglustat, an inhibitor of glycosphingolipid biosynthesis, or 2-hydroxypropyl-␤ -cyclodextrin (HP-␤ -CD), a cholesterol-binding agent, alleviates neuronal ganglioside (miglustat and HP-␤ -CD) and cholesterol (HP-␤ -CD) storage in the NPC1 mouse model, and markedly prolongs survival in NPC1 mouse and cat models (21)(22)(23)(24)(25)(26). These promising preclinical studies have led to administration of HP-␤ -CD in four NPC1 patients through the investigatorsponsored single-patient Investigational New Drug program in the USA and two NPC1 patients in Japan ( 27 ), and laid the groundwork for a Phase 1 trial for HP-␤ -CD that was initiated in January 2013 at the National Institutes of Health (NIH).…”

Development of targeted therapies for Parkinson's disease and related synucleinopathies

“…Treatment of NPC mice with miglustat resulted in improvements of survival in these mice ( 41 ). In a cat model of NPC disease, miglustat delayed the onset of neurological symptoms and improved survival ( 42 ). These effects were associated with improved survival of cerebellar Purkinje cells and reduced micogliosis and infl ammatory markers.…”