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

Abstract

Background: "Chaperones" may enhance mutant enzyme activities, but therapeutic levels have not been shown in vivo. Results: A chaperone, isofagomine, stabilizes wild type and mutant acid ␤-glucosidases in tissues and sera and reduces visceral substrates in vivo. Conclusion: These effects are enhanced pre-versus postsynthetically. Significance: The results are proof of principle for the potential therapeutic use in residual enzyme diseases.

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

“…My data supports those of others (Sun et al, 2012;; Bendikov-Bar et al, 2013; by confirming that the GBA mutation is associated with a reduction in GCase activity. However, the level of GCase activity varied between mutations and is to some degree, patient dependent.…”

“…Both have been shown to significantly increase GCase activity in human fibroblasts (Sun et al, 2012;; Bendikov-Bar et al, 2013). Studies in fibroblasts derived from homozygous and heterozygous GBA mutation carriers, revealed the expected range of reduction in GCase activity: severe in GD patients, intermediate in heterozygous carriers and unaffected in PD patients without mutations .…”

“…This effect was also seen in controls. IFG has also been shown to increase residual GCase activity in fibroblasts originating from type 1 GD patients (Chang et al, 2006;; Steet et al, 2006) and also in mice homozygous for GBA mutations (Sun et al, 2012).…”

“…ambroxol and isofagomine, have been shown to bind mutant misfolded GCase stalled in the ER, assisting in the refolding and passage to the lysosome, where the chaperone-enzyme complex dissociates in the low pH and the residual activity of the enzyme can hydrolyse substrate (Sun et al, 2012;; Bendikov-Bar et al, 2013). …”

Glucocerebrosidase Mutations in Parkinson Disease

“…A number of investigations into the use of gene therapy to augment GCase levels in GBAmutation carrying models and models of PD, through adeno-associated virus-mediated (AAV-mediated) expression of GCase in the CNS via cerebral injections has found hugely beneficial effects [88,89], which serves as an excellent proof of concept for the use of GCase activity augmentation in the reduction of alpha-synuclein accumulation and transmission [89,90], and neurodegeneration in PD models [88], which will be an avenue to pursue further with a view to translation to human PD patients.…”