Niemann-Pick Knowledge Centre
(Type C)
Treatment
Specific Therapies
Specific therapies for the intended treatment of NPC are based on targeting known pathophysiological and/or biochemical defects involved in the pathogenesis of the disease. While earlier attempts proved largely ineffective, more recent efforts indicate possible hope for the future.
Oral substrate reduction therapy
Oral substrate reduction therapy (SRT) is an oral therapy that works by reducing the amount of substrate the cells make so there is less for the naturally occurring enzyme to break down. This means that even though the body makes less enzyme, the enzyme that is made is more able to keep the body system in balance.
Miglustat (Zavesca®) is the first approved therapy in the EU for Niemann Pick Type C (NPC).
Ed Wraith, M.D., Royal Manchester Children's Hospital, commented: "For the first time we have an approved therapy for NPC. The data on the effects of treatment with Zavesca® obtained in a clinical trial and in a retrospective cohort study consistently showed a favorable clinical response. As a treating physician I am acutely aware of the importance of reducing progression of neurological symptoms." Read more about the clinical trial.
Zavesca is the first treatment to give hope to patients with NP-C and offers the following benefits:
- Zavesca stabilizes or slows down progression of key neurological symptoms in patients with NP-C19,20,21
- Zavesca is generally well tolerated when administered at 200 mg three times a day in patients with NP-C21
- Stabilization of neurological disease progression is now a realistic goal achievable for many NP-C patients with Zavesca
Download the Zavesca Summary of Product Characteristics (SmPC) 
Bone marrow and liver transplantation
A number of studies have established that bone marrow transplantation or combined bone marrow and liver transplantation are ineffective in treating the neurological symptoms of NPC1.1,2,5,6 In theory, bone marrow transplantation (BMT) may benefit patients with NPC2 gene mutations as the NPC2 protein is a lysosomal glycoprotein and BMT has been used successfully in other lysosomal enzyme deficiency disorders. Liver transplantation in humans corrects hepatic dysfunction, but does not ameliorate the neurologic disease.
Replacement or repair of gene or gene product
The most common NPC gene product, NPC1 protein, is not suitable for transduction therapies, and NPC1 gene replacement or repair is not yet practicable.
Cholesterol depletion
A trial with different combinations of cholesterol-lowering agents (cholestyramine, lovastatin, nicotinic acid and imethyl sulfoxide [DMSO]) was performed in 25 patients to assess the effects of reducing tissue and plasma levels of free cholesterol in NPC.7 Although all treatment regimens except DMSO reduced hepatic and plasma cholesterol levels, no effect on the neurologic symptom progression was identified.1,7
Cell-signalling targets
Studies have demonstrated that direct or indirect over-expression of the GTPase enzyme, Rab 9, can reverse the NPC phenotype (i.e., restore lipid trafficking) in tissue culture.8,9 Although not yet tested in human trials, this suggests mobilisation of endosomal cargoes as a potential target for small-molecule therapies. Laboratory studies of cellular and mouse NPC models have suggested interruption of apoptosis and related routes of cell death and dysfunction as a possible therapeutic target in NPC.10 A putative compound (NP-27) has been identified that partially corrects the NPC biochemical phenotype in cell culture by stimulating cholesterol transport pathways and restoring LDL stimulation of cholesterol esterification in cultured cells from NPC mice.11 Future plans for this compound are not known.
Neurosteroids
Neurosteroids are steroids synthesised in the brain that affect neuronal growth and differentiation during development, and which modulate a variety of neurotransmitter receptors. NPC1 mutant mice exhibit a normal capacity to synthesise neurosteroids during embryonic/foetal development, but lose this ability in the early neonatal period, prior to onset of neurological symptoms.12,13 This suggests a possible role for neurosteroid replacement as a therapy in NPC.
Preliminary studies of neurosteroid replacement with allopregnanolone, given as a single injection or repetitively in mouse models of NPC, have indicated delayed demyelination and symptom onset, reduced lipid accumulation, and improvements in survival provided that treatment is initiated early in post-natal life.14–16 The mechanisms by which these effects take place are not fully known, although GABAA receptors are believed to play some role, possibly in conjunction with pregnane X receptors.13,16
Glycosphingolipid synthesis inhibition
The use of inhibitors of glycosphingolipid synthesis is showing promise as a possible treatment for NPC, offering a means of breaking the lipid trafficking gridlock.17 Inhibition of glycosphingolipid synthesis by miglustat has been shown to delay symptom onset and prolong survival in both murine and feline models of NPC.18 A recent case study of one year of miglustat therapy in two children with NPC (aged 9 and 14 years) reported improvements in CNS symptoms and stabilisation of systemic disease.4 Improvements were seen in assessments of movement, swallowing ability and aspects of cognition.
A 24-month, randomised, controlled clinical trial of miglustat in 29 patients with juvenile/adult NPC (with a sub-study in 12 paediatric patients) has recently been completed. Preliminary data from the first 12 months on treatment indicate that miglustat improved or stabilised several clinically relevant markers of the disease; saccadic eye movements, cognition, auditory acuity and ambulation.3 This is the first treatment studied in NPC for which there are clinical data supporting a disease-modifying benefit.3
Miglustat is still under investigation for the treatment of patients with NPC, and is currently approved in the European Union, the United States, Australia, Canada, Switzerland, Brazil and Israel for the treatment of patients with mild-to-moderate type 1 Gaucher disease who are unsuitable for enzyme replacement therapy.
References:
1. Patterson MC, Vanier MT, Suzuki K et al. Niemann–Pick disease, type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th ed, 2001. New York: McGraw-Hill, Ch 145, pp 3611–33.
2. Patterson MC. Niemann–Pick disease Type C. Gene Reviews 2007a (updated 9 July). Accessible at: www.geneclinics.org. Accessed 28th May 2009.
3. Patterson MC, Vecchio D, Prady H et al. Miglustat in Niemann−Pick type C disease: Results of the first 12 months treatment. Lancet Neurol 2007b, July 30; [Epub ahead of print].
4. Chien YH, Lee NC, Tsai LK et al. Treatment of Niemann–Pick disease type C in two children with miglustat: Initial responses and maintenance of effects over 1 year. J Inherit Metab Dis 2007, June 21; [Epub ahead of print].
5. Sakiyama T, Tsuda M, Owada M et al. Bone marrow transplantation for Niemann–Pick mice. Biochem Biophys Res Commun 1983;113:605–10.
6. Yasumizu R, Miyawaki S, Sugiura K et al. Allogeneic bone marrow-plus-liver transplantation in the C57BL/ KsJ spm/spm mouse, an animal model of Niemann–Pick disease. Transplantation 1990;49:759–64.
7. Patterson MC, Di Bisceglie AM, Higgins JJ et al. The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann–Pick disease type C. Neurology 1993;43:61–4.
8. Choudhury A, Dominguez M, Puri V et al. Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann–Pick C cells. J Clin Invest 2002;109:1541–50.
9. Walter M, Davies JP, Ioannou YA. Telomerase immortalization upregulates Rab9 expression and restores LDL cholesterol egress from Niemann–Pick C1 late endosomes. J Lipid Res 2003;4:243–53.
10. Patterson MC, Platt F. Therapy of Niemann–Pick disease, type C. Biochim Biophys Acta 2004;1685:77–82.
11. Liscum L, Arnio E, Anthony M et al. Identifi cation of a pharmaceutical compound that partially corrects the Niemann–Pick C phenotype in cultured cells. J Lipid Res 2002;43:1708–17.
12. Griffin LD, Gong W, Verot L et al. Niemann–Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 2004;10:704–11.
13. Mellon SH, Gong W, Schonemann MD. Endogenous and synthetic neurosteroids in treatment of Niemann– Pick Type C disease. Brain Res Rev 2007 Jun 12; [Epub ahead of print].
14. Mellon SH, Griffi n LD. Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab 2002;13:35–43.
15. Ahmad I, Lope-Piedrafita S, Bi X et al. Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann–Pick C mice. J Neurosci Res 2005;82:811–21.
16. Langmade SJ, Gale SE, Frolov A et al. Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann–Pick C disease. Proc Natl Acad Sci USA 2006;103:13807–12.
17. Lachmann RH, te Vruchte D, Lloyd-Evans E et al. Treatment with miglustat reverses the lipid-trafficking defect in Niemann–Pick disease type C. Neurobiol Dis 2004;16:654–8.
18. Zervas M, Somers KL, Thrall MA, Walkley SU. Critical role for glycosphingolipids in Niemann–Pick disease type C. Curr Biol 2001b;11:1283–7
19. Patterson MC, et al. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007; 6:765–772.
20. Data on file – Retrospective cohort study 1. 2008.
21. Patterson MC, et al. Miglustat in Niemann-Pick disease Type C (NPC): long-term data from a clinical trial. ASHG 58th Annual Meeting 2008; poster 766.
© 2007 Blackwell Publishing Limited. Reproduced by permission.