New agents and approaches to treatment in Niemann-Pick type C disease

Niemann-Pick disease type C is an autosomal recessive disorder caused by mutations in either one of the two genes, NPC1 or NPC2, which encode proteins involved in the regulation of normal transport and/or processing of free cholesterol. Several types of lipids including free cholesterol (unesterified), sphingosine, sphingomyelin, phospholipids and glycosphingolipids (glucosylceramide and gangliosides GM2 and GM3) are accumulated in lysosomes and late endosomes of cells, with pronounced concentrations in the liver and the spleen. The key laboratory diagnostic test for NP-C is filliping staining of cultured skin fibroblasts from the patient, to demonstrate free cholesterol accumulation in lysosomes secondary to impaired intracellular cholesterol transport. The symptomatology and rate of disease progression are strongly influenced by age at disease onset and different clinical forms have been described on this basis: Perinatal, Early-infantile (EI), late-infantile (LI), juvenile and adult forms. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Nowadays there is no fully effective treatment, only supportive measures for relief of specific manifestations of the disease. The intervention to slow disease progression is the most promising therapy. A number of experimental disease - specific therapies, based on the molecular pathology of NP-C, have been tested in cell culture and animal models including neurosteroids, cholesterol - binding agents, curcumin and Miglustat. This paper summarizes the recent developments that have been investigated for the treatment in patients and animal models with NPC. Current therapeutic approaches have been classified based on the targeting of cellular function, the anti - apoptotic cellular mechanisms and the stem cells therapy.