skip to content
Dovepress - Open Access to Scientific and Medical Research
View our mobile site

8852

Gaucher disease: clinical profile and therapeutic developments

Review

(2401) Views  (892) Full article downloads

Authors: Timothy M Cox

Published Date December 2010 Volume 2010:4 Pages 299 - 313
DOI: http://dx.doi.org/10.2147/BTT.S7582

Timothy M Cox
Department of Medicine, University of Cambridge, Cambridge, UK

Abstract: Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme®), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV® (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential 'niche busters'. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.

Keywords: Gaucher disease, orphan diseases, lysosome, macrophage, enzyme therapy, substrate inhibitors, enzyme replacement




 

Other articles by Professor Timothy Cox



Readers of this article also read:

Review of the safety and efficacy of imiglucerase treatment of Gaucher disease
Palliative treatment of malignant ascites: profile of catumaxomab
Managing idiopathic short stature: role of somatropin (rDNA origin) for injection
Optimal therapy in Gaucher disease
Vitamins D, C, and E in the prevention of type 2 diabetes mellitus: modulation of inflammation and oxidative stress
Gut microbiota: next frontier in understanding human health and development of biotherapeutics
Effects of rituximab treatment on the serum concentrations of vitamin D and interleukins 2, 6, 7, and 10 in patients with rheumatoid arthritis
Imiglucerase in the treatment of Gaucher disease: a history and perspective
New option for management of HIV-1 infection in treatment-naive patients: once-daily, fixed-dose combination of rilpivirine-emtricitabine-tenofovir
Role of gabapentin enacarbil XR in restless legs syndrome
  • Testimonials

    "... I was impressed at the rapidity of publication from submission to final acceptance." Dr Edwin Thrower, PhD, Yale University

  • Journal Indexing

    See where all the Dove Press journals are indexed