New prospects for the treatment of lysosomal storage diseases.
Although individually rare, lysosomal storage disorders constitute a significant burden on society. To date, enzyme replacement therapy (ERT) has been the most successful therapeutic approach for lysosomal storage disorders. ERT reverses systemic manifestations of Gaucher disease but does not effectively treat the neurological complications. Recently, ERT produced a reduction of severe neuropathic pain, stabilisation of renal disease, and improved vascular function and structure in short-term, placebo-controlled trials in patients with Fabry's disease. Long-term studies are necessary to evaluate the full potential of ERT in this disease. In patients with Pompe disease, a fatal cardiac and skeletal muscle disorder, ERT improved cardiac function and structure, and increased overall muscle strength. It has already increased survival in a small number of affected infants. ERT also decreased liver and spleen size, joint mobility and quality of life in patients with mucopolysaccharidosis type I, but when the therapeutic protein is administered intravenously, it is unlikely to modify the neurological outcome in this or in other similar disorders. Bone marrow transplantation continues to be effective in Gaucher disease, in some forms of mucopolysaccharidosis and in mild forms of Krabbé disease, but it has high morbidity and mortality that limits its use in lysosomal storage disorders. Drugs that slow the rate of formation of accumulating glycolipids are being developed and one of them, OGT-918 (N-butyldeoxynojirimycin), is showing promise in patients with Gaucher disease. Gene therapy for lysosomal storage disorders holds promise as a replacement for the other therapies described here but requires much more development before clinical efficacy trials.
Schiffmann
Raphael
R
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1260, USA. RS4e@nih.gov
Brady
Roscoe O
RO
D016026:Bone Marrow Transplantation; D000795:Fabry Disease / Q000628:therapy; D005776:Gaucher Disease / Q000628:therapy; D015316:Genetic Therapy; D005962:Glucosylceramidase / Q000627:therapeutic use; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000628:therapy*; D009083:Mucopolysaccharidoses / Q000628:therapy
D005962:Glucosylceramidase