Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene, which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. Gaucher disease is the most prevalent of the lysosomal storage disorders.1
Gaucher disease has been divided into three subtypes according to the presence (or absence) of neurological involvement.2 Type 1 Gaucher disease is the most common form; symptoms include bone disease, enlarged liver and spleen, anemia, and low platelet count. Type 2 Gaucher disease is characterized by CNS damage and is typically fatal during the first three years of life.2 Type 3 Gaucher disease also includes CNS involvement, but is much more mild and slowly progressive compared to Type 2.
There is no cure for Gaucher disease, but one approach for the treatment of Type 1 Gaucher disease is enzyme replacement therapy (ERT). Patients who receive ERT are treated intravenously with a biosynthetic version of the missing enzyme. A rodent-based cell line ERT has been on the market for 15 years and a plant-based cell line ERT is currently in clinical trials.
Shire’s ERT for Type 1 Gaucher disease, VPRIV™ (velaglucerase alfa for injection), is derived from a human fibroblast cell line, HT-1080. HT-1080 cells are a well-characterized human cell line and are being used or investigated by Shire in several on-market and in-pipeline treatments.
Shire’s human cell line technology platform produces proteins that more closely resemble the naturally occurring human glycosylation patterns or sugar molecules on the protein surface. In contrast to plant and rodent cell lines, proteins derived from human cells are theoretically less likely to produce antibodies or trigger an immune response in patients.
All patients enrolled in the Phase 3 clinical studies for VPRIV underwent a comprehensive panel of tests that were developed and validated to assess antibody response. In each study, samples were first screened using an electrochemiluminescence (ECL) assay. Positive samples were confirmed using a quantitative radioimmunoprecipitation (RIP) assay. Positive cut-points were established for the ECL assay at 5 ng/mL in terms of fixed raw counts and for the RIP assay at 4 ng/mL. The results suggest significant antigenic differences between velaglucerase alfa and imiglucerase—the ERT derived from a rodent cell line—with velaglucerase alfa producing only a 1% seroconversion rate compared to 23% for imiglucerase.
VPRIV was approved by the Food and Drug Administration (FDA) for the treatment of Type 1 Gaucher disease in pediatric and adult patients on Feb. 26, 2010.
1. Cox TM, Schofield JP. Gaucher’s disease: clinical features and natural history. Baillieres Clin Haematol. 1997;10(4):657-689.
2. Desnick RJ. Gaucher disease: a century of delineation and understanding. Prog Clin Biol Res. 1982; 95:1-30.
This article was published in Drug Discovery & Development magazine: Vol. 13, No. 3, April 2010, p. 11.
Filed Under: Drug Discovery