Niemann-Pick Disease
healthcare needs of patients (and their cost implications) and to evaluate the long-term effects of therapies in development.45
Current Therapeutic Options Supportive Measures
Management of NPC has traditionally been with symptomatic treatments that alleviate aspects of the disease and improve quality of life.46
For instance, physicians frequently treat dystonia and tremor with anticholinergic, beta-blocking and antispasmodic drugs, dystonia in some patients with levodopa and seizures with antiepileptic medications. Tricyclic antidepressants and central nervous system stimulants may help in controlling cataplexy.50,51
Similarly, antipsychotics
are generally used to manage secondary psychiatric illnesses, particularly schizophrenia, with a preference for lower-potency or atypical agents that are less likely to cause or worsen dystonia. Speech therapy to minimise the risk of aspiration and physiotherapy for gait disturbances can be effective in reducing the risks associated with these clinical manifestations of NPC. These supportive measures prolong the lives of patients by preventing hospitalisations from falls or aspirations, which can often lead to pneumonia and death. While these therapeutic options can lessen the burden of NPC, they do not alter the underlying course of the disease or specifically target NPC.
Cholesterol-lowering Agents
As cholesterol has been thought to be an offending metabolite in NPC, a strategy that had been put forward for treating this disease was to use various cholesterol-lowering agents in an attempt to decrease intracellular cholesterol storage in patients.46
Although certain
combinations of cholestyramine, lovastatin, nicotinic acid or dimethyl sulphoxide did lower unesterified cholesterol levels in the liver and blood with minimal side effects, there has been no evidence showing any appreciable clinical benefit.52,53
Targeted Therapy
Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) was recently approved for the treatment of the progressive neurological manifestations of NPC in adults, adolescents and children in a number of countries, including those of the EU.54
is capable of crossing the blood–brain barrier55
This small iminosugar molecule and acts as a reversible
competitive inhibitor of glucosylceramide synthase, which normally catalyses the first committed step in glycosphingolipid synthesis.56,57
By
reducing the activity of this enzyme, miglustat decreases the production of the toxic GM2 and GM3 gangliosides,46 disease-modifying therapy for NPC.
and it is the first approved
Encouraging data from pre-clinical studies in murine and feline NPC models58 trial.59
eventually led to a prospective randomised controlled clinical
In this trial, NPC patients 12 years of age and older (n=29) were randomised to receive either miglustat at a dose of 200mg three times a day (n=20) or standard care (n=9) for 12 months, while another cohort of children less than 12 years of age (n=12) were given miglustat at a dose adjusted for body surface area. The primary end-point for all subjects was disease progression based on horizontal saccadic eye movement (HSEM) velocity.
After 12 months, patients treated with miglustat showed improvement in HSEM velocity compared with those receiving standard care.59
The
difference in improvement reached statistical significance when individuals using benzodiazepine medications, which are known to affect SEM, were excluded from both groups. Swallowing capacity and
86 Treatments in Development
Although miglustat is currently the only agent that has been tested in humans, several drugs have shown some benefit in pre-clinical studies in animal models. The histone deacetylase inhibitor valproic acid was able to enhance neuronal differentiation and restore impaired astrocytes in defective neural stem cells in NPC1-/- mice; this treatment reduced cholesterol levels, thereby promoting cholesterol homeostasis in the brain.61
Imatinib therapy inhibits the
proapoptotic c-Abl/p73 system and was shown to preserve Purkinje neurons and reduce cell apoptosis in the cerebellum in addition to improving neurological symptoms and increasing survival of NPC mice.62
Neither of these treatments has been
trialled in adult NPC patients, although the use of valproic acid for mood disorders has been described in adolescent and adult patients with neuropsychiatric disease.3,12
Recent data demonstrated that early treatment with sterol-binding agents such as 2-hydroxy-β-cyclodextrin in NPC mice could substantially decrease cholesterol concentrations in the liver and spleen while improving both liver dysfunction and neurodegeneration.63 Derived from the common spice turmeric, curcumin is a potent antioxidant and may also have positive effects on NPC disease.21 Additional data from clinical studies will be required to confirm these promising outcomes and assess the long-term effects these drugs have in humans.
The Future of Niemann-Pick Disease Type C Research and Management
Much remains unclear about the neuropathology of NPC. A better understanding of the underlying pathophysiology of NPC will allow for the development of more targeted treatments to join miglustat in the armamentarium of tools available for treating NPC. There are many potential points in the pathway of glycosphingolipid synthesis that may be altered by targeted small molecules. Therapies that are able to stop the progression of the disorder or prevent its onset in persons carrying the mutation would be of great value. This would
EUROPEAN NEUROLOGICAL REVIEW
stable auditory acuity improved in treated individuals over 12 years of age and a slower deterioration in ambulatory index was observed. Adverse events were largely mild to moderate in severity, with the most frequent negative effects associated with treatment being diarrhoea, flatulence, weight loss and abdominal pain. Two patients 12 years of age and older and one child receiving miglustat withdrew from the study due to an adverse event. Overall, miglustat was shown to stabilise neurological disease over 12 months with acceptable safety and tolerability.59
A non-controlled, open-label extension60 of the above trial allowed
As miglustat is currently the only targeted treatment available for NPC, a strong argument exists that it should be offered as soon as symptoms are observed and a diagnosis is made in order to minimise and arrest neuronal loss, and potentially to alter the illness course. The relatively brief clinical experience with miglustat limits any conclusions in terms of how long it may delay sentinel medical events, the need for full nursing care or death. Studies are ongoing to determine its effect on these disease end-points.
patients to continue using miglustat for a further 12 months for a total of up to 24 months of treatment. These long-term data further supported findings that miglustat therapy stabilises neurological disease in NPC patients and is well tolerated in both adults and children.60
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