Current and Future Stategies for the Treatment of Metabolic Storage Disorders
R.O. Brady
National Institute of Neurological Disorders and Stroke, Building 10 Room 3D04, National Institutes of Health, Bethesda, MD, USA 20892-1260, USA
Following the unprecedented success of enzyme replacement therapy (ERT)
in patients with Type 1 (non-neuronopathic) Gaucher disease, this
therapeutic approach has been applied to a number of other hereditary
metabolic storage disorders of humans. I shall discuss the responses
to ERT in patients with Fabry disease, Hurler disease, Maroteaux-Lamy
disease and Pompe disease. Because impairment of the central nervous
system does not improve with ERT alone, additional therapeutic
modalities have been initiated to treat patients with brain
involvement. Substrate reduction therapy (SRT) has been examined in
patients with late-onset Tay-Sachs disease and in patients with Type C
Niemann-Pick disease. SRT combined with ERT is currently being
evaluated in patients with Type 3 (chronic-neuronopathic) Gaucher
disease. Another potential approach is the use of molecular
chaperones to augment residual catalytic activity of mutated enzymes.
Investigations of this strategy have shown promise in a murine model of
juvenile generalized (GM1) gangliosidosis. Other studies provided the
foundation for a safety and dose-escalation trial of molecular
chaperone therapy in patients with Fabry disease. Finally, the present
status of gene editing and gene therapy in metabolic storage diseases
will be summarized.
Key words:
Enzyme replacement, substrate reduction, chaperone
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