Gaucher disease is an inherited metabolic disease caused by genetic acid β -glucosidase (GBA) deficiency and is currently treated by enzyme replacement therapy.
This study provides novel pharmacokinetic data that support current imiglucerase administration regimens and suggests the existence of a glucocerebrosidase activity threshold related to Gaucher disease type 1 aggressiveness.
Together, this comprehensive data set supports the treatment of adult and paediatric patients with GD who are naïve to ERT or who have previously been treated with imiglucerase.
We investigated the long-term development of B cell malignancies in an authentic model of non-neuronopathic Gaucher's disease in mice: selective deficiency of β-glucocerebrosidase in haematopoietic cells [Gba(tm1Karl/tm1Karl)Tg(Mx1-cre)1Cgn/0, with excision of exons 9-11 of the murine GBA1 gene, is induced by poly[I:C].
This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase.
This analysis provides a benchmark for evaluating the utility of a disease management approach for GD1 based on monitoring achievement of therapeutic goals after treatment with imiglucerase.
Posttranslationally engineered human beta-glucocerebrosidase (Ceredase/Cerezyme) is commercially available and is the standard ERT for Type I Gaucher disease.
Ann Allergy 72: 1994: 395-403) and glucocerebrosidase for Gaucher disease (Niederau C, vom Dahl S, Haussinger D. First long-term results of imiglucerase therapy of type 1 Gaucher disease.Eur J Med Res 1998: 3: 25-30).
About 30 identified missense mutations are causal to the defective activity of acid beta-glucosidase in this disease. cDNAs were characterized from a moderately affected 9-year-old Ashkenazi Jewish Gaucher disease type 1 patient whose 80-year-old, enzyme-deficient, 1226G (Asn370----Ser [N370S]) homozygous grandfather was nearly asymptomatic.
Genotypes at the acid beta-glucosidase locus in selected Gaucher disease Type 1 patients were determined by allele-specific oligonucleotide hybridization of amplified genomic DNA.
These kinetic, immunologic, and thermostability studies indicated that 1) type 1 Gaucher disease is biochemically heterogeneous and results from at least four distinct allelic acid beta-glucosidase mutations that alter enzyme structure and/or function, 2) neuronopathic and non-Jewish non-neuronopathic phenotypes cannot be distinguished reliably by kinetic analyses alone, and 3) the Ashkenazi type 1 Gaucher disease results from a unique mutation that alters a specific active site domain of acid beta-glucosidase.
These inhibition studies indicated that: Gaucher disease type 1 is biochemically heterogeneous, neuronopathic and non-Jewish nonneuronopathic phenotypes cannot be reliably distinguished by these inhibitor studies, and the Ashkenazi Jewish form of Gaucher disease type 1 results from a unique mutation in a specific active site domain of acid beta-glucosidase that leads to a defective enzyme with a decreased Vmax.
Although reduced acid beta-glucosidase activity appears to be the primary enzyme defect in type I Gaucher disease, patients with this disorder also have marked elevation of serum acid phosphatase and beta-hexosaminidase activities but with a normal level of lactic dehydrogenase activity.