Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

Abstract

The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates.

Ex Vivo and in Vivo Effects of Isofagomine on Acid β-Glucosidase Variants and Substrate Levels in Gaucher Disease

“…In spleen and brain, a lesser but significant effect occurred with the hGCase, but no effect was detected on the endogenous V394L GCase, indicating that these tissues were exposed to lower concentrations of IFG. As an example, there was a lack of major effect from IFG treatment in the CNS of a V394L-based model (28).…”

Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease

“…Ambroxol and isofagomine are two orally active, brain-penetrant small-molecule chaperones that have been investigated for their ability to increase mutant GCase activity in GD fibroblasts (17,18) and in a mouse model (19). The degree to which the enzyme activity can be increased depends in part on the GBA mutation, but has been seen in the two commonest GD mutations, N370S and L444P.…”

Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease

“…Recent insight into the misfolding of GCase has led to the development of pharmacological chaperones, such as isofagomine, that are designed to aid in the proper folding and delivery of GCase to the lysosome. These agents increase lysosomal delivery of several mutant variants of GCase in vitro (26,27) and in preclinical animal models have also shown efficacy in restoring GCase activity, further suggesting that modulating protein stability can provide therapeutic benefits for GD (28). Currently, pharmacological chaperones are under investigation in phase II and phase III clinical trials for the treatment of type I GD and other lysosomal storage diseases (29,30).…”