New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Zavesca®), a reversible inhibitor of glycosphingolipid synthesis, has recently been authorized in the European Union, Brazil and South Korea for the treatment of progressive neurological symptoms in adult and pediatric patients, and represents the first specific treatment for NP-C. Here we review current data on the pharmacology, efficacy, safety and tolerability of miglustat in patients with NP-C, based on findings from a prospective clinical trial, preclinical and retrospective studies, and case reports. Findings demonstrated clinically relevant beneficial effects of miglustat on neurological disease progression in adult, juvenile and pediatric patients with NP-C, particularly those diagnosed in late childhood (6–11 years) and in juveniles and adults (12 years and older), compared with those diagnosed in early childhood (younger than 6 years). Miglustat therapy was well-tolerated in all age groups. With the approval of miglustat, treatment of patients with NP-C can now be aimed toward stabilizing neurological disease, which is likely the best attainable therapeutic goal for this disorder

Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials

Background: Niemann-Pick disease type C (NPC) is a lysosomal storage disease with a heterogeneous neurodegenerative clinical course. Multiple therapies are in clinical trials and inclusion criteria are currently mainly based on age and neurological signs, not taking into consideration differential individual rates of disease progression. Results: In this study, we have evaluated a simple metric, denoted annual severity increment score (ASIS), that measures rate of disease progression and could easily be used in clinical practice. We show that ASIS is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria. In addition, we show that ASIS has prognostic value and demonstrate that treatment with an experimental therapy - acetyl-DL-leucine - is associated with a reduction in ASIS scores. Conclusion: ASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy

Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders

Additional file 1: Table S1. of Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database

Comparison of sibling profiles. (DOCX 42 kb

Additional file 1 of The burden of disease in metachromatic leukodystrophy: results of a caregiver survey in the UK and Republic of Ireland

Supplementary Material