Difficulties with delivery of functional enzyme to the brain limit the ability to modify neurologic outcome in patients with neuronopathic forms of the lysosomal storage diseases. In a subset of these disorders, which result from a disruption of glycosphingolipid metabolism, the use of a small molecule inhibitor of substrate precursor synthesis may reduce the amount of brain tissue lipid deposition and lead to amelioration of disease. The efficacy of this approach, termed substrate reduction therapy, has been demonstrated in several animal models; with resultant reduction of ganglioside storage in the brain, delayed onset of symptoms and prolonged survival. This pre-clinical proof of therapeutic concept served as the rationale for proceeding with trials in humans using miglustat; an imino-sugar inhibitor of ceramide-specific glucosytransferase (the catalyst for the first committed step in glycosphingolipid synthesis). The glycosphingolipidoses are rare orphan disorders; the limited number of suitable study subjects and the paucity of information on the natural history of these disorders represent major hurdles in the conduct of clinical trials. As treatment potentially constitutes lifelong administration, there will be a need to identify any potential safety considerations attendant to the use of these agents. With greater understanding of disease mechanism, adjunctive therapies may be identified; offering the prospect of modifying these otherwise relentlessly progressive neurodegenerative diseases.
Keywords: Lysosomal storage disorders, neurodegenerative disease, GM2-gangliosidosis, Niemann-Pick type C
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