[PS8-1D-3] Lysosomal storage disorders; potential approaches for CNS diseases
Lysosomal storage disorders (LSDs) are inherited metabolic disorders with lysosomal enzyme deficiency caused by the specific encoding gene mutations, which leads to progressive accumulation of undigested substrates in various tissues. Lysosomal enzymes are ubiquitously expressed, therefore symptoms of LSDs are multisystemic including the central nervous system (CNS).
Until 1990, only symptomatic care are available. In 1991, enzyme replacement therapy (ERT) was approved for the treatment of Gaucher disease. Since then, several LSDs have been successfully treated by ERT. Substrate reduction therapy through inhibition of glucosylceramide synthase has also been approved for Gaucher disease and Niemann-pick disease type C.
While these therapies address most of the visceral manifestations, none are effective against CNS disease because of its inability to cross the blood-brain barrier (BBB). A number of different therapeutic strategies are being investigated to settle CNS treatment issues, including intrathecal/intraventricular administration of recombinant enzyme, transplantation of bone-marrow/hematopoietic stem cells, and gene therapy.
Pharmacological chaperone therapy (PCT) using BBB permeable small-molecules is also being explored as a potential approach for neuronopathic LSDs. PCT is based on oral administration of stabilizer of mutant proteins. Pharmacological chaperones are designed to selectively bind to a mutant enzyme protein and can increase enzyme stability, catalytic activity, and lysosomal translocation, resulting in the recovery of their function. We have so far been developing PCT, and especially are proactive in clinical application. In this presentation, the development of CNS-targeted therapies for LSDs will be outlined, followed by the utility of PCT in patients with neuronopathic Gaucher
Until 1990, only symptomatic care are available. In 1991, enzyme replacement therapy (ERT) was approved for the treatment of Gaucher disease. Since then, several LSDs have been successfully treated by ERT. Substrate reduction therapy through inhibition of glucosylceramide synthase has also been approved for Gaucher disease and Niemann-pick disease type C.
While these therapies address most of the visceral manifestations, none are effective against CNS disease because of its inability to cross the blood-brain barrier (BBB). A number of different therapeutic strategies are being investigated to settle CNS treatment issues, including intrathecal/intraventricular administration of recombinant enzyme, transplantation of bone-marrow/hematopoietic stem cells, and gene therapy.
Pharmacological chaperone therapy (PCT) using BBB permeable small-molecules is also being explored as a potential approach for neuronopathic LSDs. PCT is based on oral administration of stabilizer of mutant proteins. Pharmacological chaperones are designed to selectively bind to a mutant enzyme protein and can increase enzyme stability, catalytic activity, and lysosomal translocation, resulting in the recovery of their function. We have so far been developing PCT, and especially are proactive in clinical application. In this presentation, the development of CNS-targeted therapies for LSDs will be outlined, followed by the utility of PCT in patients with neuronopathic Gaucher