8 Treatment Options for Np-C: Changing Our Approach to the Disease

Abstract

Definitive disease-modifying therapy for Niemann-Pick disease, type C (NPC) would either correct the primary genetic defect or replace the deficient gene product [1]. Neither strategy is currently applicable to patients with NPC1 mutations, but replacement of the NPC2 protein by haematopoietic stem cell transplantation is theoretically possible, although proof of principle in humans is lacking. Alternative approaches involve interdicting pathways downstream to the primary mutation that lead to cellular dysfunction. These approaches include reduction of substrate burden, replacement of deficient downstream products, suppression of inflammation, inhibition of apoptosis and activation of alternate pathways. Of these approaches, only substrate reduction therapy has been studied and approved for use in humans. Miglustat is an iminosugar that competitively inhibits glucosylceramide synthase, the enzyme catalysing the rate-limiting step in the synthesis of higher order glycosphingolipids. Miglustat has been shown to delay the onset of symptoms in the NPC murine model. Both prospective and retrospective human studies have also found evidence of a beneficial effect on disease progression in NPC [2-5]. The availability of such a treatment mandates early diagnosis of patients with NPC, since those without irreversible disease will be likely to benefit most. Currently, there is no readily available test for NP-C, but in future, oxysterols or other biomarkers may facilitate screening for NPC. Guidelines have been published for the general medical management of people with NPC [6]. It is essential that physicians take a comprehensive approach to managing NPC, since patients are most likely to benefit when disease-modifying therapy is combined with meticulous general medical care and symptom management.