sphingosine-phosphorylcholine and Niemann-Pick-Disease--Type-A

Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures.

Topics: Adult; Biomarkers; Bone Density; Enzyme Replacement Therapy; Female; Hexosaminidases; Humans; Lipids; Liver; Lung; Male; Niemann-Pick Disease, Type A; Phosphorylcholine; Recombinant Proteins; Sphingomyelin Phosphodiesterase; Sphingosine; Spleen; Treatment Outcome

Acid sphingomyelinase deficiency (ASMD) is a lysosomal disorder caused by deficiency of acid sphingomyelinase (ASM) leading to the accumulation of sphingomyelin (SM) in a variety of cell types. Lysosphingomyelin (LysoSM) is the de-acetylated form of SM and it has been shown as a biomarker for ASMD in tissues, plasma, and dried blood spots (DBS) and lysosphingomyelin-509 (LysoSM509) is the carboxylated analogue of LysoSM. High levels of Lysosphingomyelin 509 (LysoSM509) have also been shown in ASMD patients. In this study, we report the utility of the quantification of LysoSM and LysoSM509 in DBS of patients from Latin America with ASMD by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).. DBS samples from 14 ASMD patients were compared with 15 controls, and 44 general newborns. All patients had their diagnosis confirmed by the quantification of ASM and the measurement of the activity of chitotriosidase. All patients had significantly higher levels of lysoSM and lysoSM509 compared to controls and general newborns.. The quantification of lysosphingolipids in DBS is a valuable tool for the diagnosis of ASMD patients and lysoSM can be useful in the differential diagnosis with NPC. This method is also valuable in the ASMD newborn screening process.

Topics: Chromatography, Liquid; Humans; Infant, Newborn; Niemann-Pick Disease, Type A; Niemann-Pick Diseases; Sphingomyelin Phosphodiesterase; Tandem Mass Spectrometry

Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Herein we present results of simultaneous LC-ESI-MS/MS measurements of lysosphingomyelin and lysosphingomyelin 509 in plasma and dried blood spots (DBS) collected from ASMd and NPC patients and suggest that the plasma but not DBS levels of the two analytes allow differential biochemical screening of ASMd and NPC.

Topics: Biomarkers; Case-Control Studies; Chromatography, Liquid; Dried Blood Spot Testing; Humans; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type B; Niemann-Pick Disease, Type C; Phosphorylcholine; Spectrometry, Mass, Electrospray Ionization; Sphingosine; Tandem Mass Spectrometry

Niemann-Pick type A is a disease characterized by the absence of a functional SMPD1 (acidic sphingomyelinase) gene and the abnormal accumulation of sphingomyelin. Under these conditions, also sphingosylphosphocholine (SPC, a sphingomyelin metabolite) accumulates in various tissues, including the brain, where it might act as a toxic stimulus, contributing to the appearance of the neurological symptoms. We studied the effects of SPC on astrocytic and neuronal cultures from rat. In particular, we investigated the possibility that SPC acts on astrocytes and that this represents the first step leading to neurodegeneration. Our results show that acute administration of SPC to astrocytes in culture promotes Ca2+ responses and a release of glutamate that, in turn, leads to cytosolic [Ca2+] elevation in neurons. We also show that chronic stimulation by SPC leads astrocytes to proliferate, but can also change their phenotype towards an activated state that might contribute to the inflammatory responses. Interestingly, upon acute SPC stimulation, activated astrocytes release more glutamate. In conclusion, we show that both chronic and acute exposure to SPC can constitute harmful signals that may have a role in the sequence of events leading to neurodegeneration.

Topics: Animals; Apoptosis; Astrocytes; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Fluorescent Dyes; Fura-2; Glutamic Acid; Hippocampus; Microscopy, Video; Necrosis; Nerve Degeneration; Neurotoxicity Syndromes; Niemann-Pick Disease, Type A; Phenotype; Phosphorylcholine; Rats; Rats, Sprague-Dawley; Sphingosine