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Gaucher disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Recognition of Gaucher disease as a reticuloendothelial storage disease was as early as 1907 [7] and, in 1924, the stored material was identified as lipid and characterized as a cerebroside [8, 9]. Identification of the sugar in this cerebroside as glucose was reported by Aghion in 1934 in his thesis for the doctorate of philosophy (Figure 90.1) [10]. The molecular defect in glucocerebrosidase (Figure 90.2) was described in 1965, independently by Brady and colleagues [11], and by Patrick [12]. The defective enzyme is a lysosomal acid β-glucosidase, active in catalyzing the release of glucose from a number of substrates in addition to glucosylceramide. There is an activator of the enzyme, saposin C, which has a low molecular weight [13]. The gene for β-glucosidase is located on chromosome 1q21 [14]. The cDNA has been cloned and a number and variety of mutations have been identified [15–17]. The type 1 disease provides an interesting therapeutic model because enzyme replacement therapy has been quite successful [18]. Bone marrow transplantation may be curative.
Fever In Inherited and Metabolic Disorders
Published in Benedict Isaac, Serge Kernbaum, Michael Burke, Unexplained Fever, 2019
This is the most common, inherited metabolic disorder of glycolipid metabolism. Excessive quantities of glucocerebroside accumulate in the cells of the reticuloendothelial system (Gaucher’s cells), due to an inherited abnormal activity of glucocerebrosidase (an intralysosomal enzyme), which catalyzes the hydrolytic cleavage of glucose from glucocerebroside. This abnormal recessive trait results in hepatosplenomegaly and bone lesions, and in certain forms involvement of the central nervous system.
Biocatalytic Nanoreactors for Medical Purposes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Oscar González-Davis, Chauhan Kanchan, Rafael Vazquez-Duhalt
Gaucher’s disease is an inherited disorder caused by deficient activity of the enzyme β-glucocerebrosidase, found mainly in lysosomes. The lack of glucocerebrosidase activity results in an accumulation of glucocerebroside in the lysosomes of macrophages, especially in the reticuloendothelial system. The accumulation of glucocerebroside leads to hepatomegaly, splenomegaly, anemia, and thrombocytopenia causing fatigue, discomfort, infections, bleeding and bruising. In addition, it induces bone related problems such as pain, bone crises, and avascular necrosis. Other problems such as lung disease, impaired growth, and delayed puberty are also associated with Gaucher’s disease (Grabowski et al., 1998; Stirnemann et al., 2017). The clinical effectiveness of the ERT has been reviewed (Grabowski et al., 1998; Connock et al., 2006). A recombinant and glycoengineered glucocerebrosidase containing mannosyl-ended oligosaccharides has been designed in order to be recognized by the specific receptors for α-mannosyl on macrophages (Oh, 2015). Also, a plant-derived variant of glucocerebrosidase has been mannosyl-targeted to disease-affected cells (Tekoah et al., 2013). Thus, the targeted delivery of enzyme for the specific treatment of Gaucher’s disease is feasible.
GlycoVHH: optimal sites for introducing N-glycans on the camelid VHH antibody scaffold and use for macrophage delivery
Published in mAbs, 2023
Loes van Schie, Wander Van Breedam, Charlotte Roels, Bert Schepens, Martin Frank, Ahmad Reza Mehdipour, Bram Laukens, Wim Nerinckx, Francis Santens, Simon Devos, Iebe Rossey, Karel Thooft, Sandrine Vanmarcke, Annelies Van Hecke, Xavier Saelens, Nico Callewaert
For example, biotherapeutics sometimes need to be endocytosed by specific cells to be effective, which can be achieved by glycan-targeting of the therapeutic protein to cell-type specific endocytic receptors. A noteworthy example in this context is the macrophage mannose receptor (MMR), a macrophage-expressed mannose-binding lectin. In Gaucher disease, the glucocerebrosidase storage product is mainly located in macrophage lysosomes, and therapy with mannosylated MMR-targeting enzyme replacement therapy is effective.9,10 Also, pathogens such as Mycobacterium, Listeria, Salmonella, Legionella, Brucella, and Acetinobacter baumanni can infect macrophages and survive and propagate intracellularly, within the phagolysosomal compartment.11 Hence, technology that enables targeting of antimicrobial agents to the macrophage phagolysosomal compartment could be used to create novel therapeutics. Antibiotics have been targeted to the MMR by incorporation into mannosylated carriers such as liposomes, microparticles, nanoparticles, or dendrimers.12–14 An expansion of this concept to VHHs could enable new antibody-mediated antimicrobial agents.15
Dual enzyme therapy improves adherence to chemotherapy in a patient with gaucher disease and Ewing sarcoma
Published in Pediatric Hematology and Oncology, 2023
Brandon Lucari, Eran Tallis, Vernon Reid Sutton, Timothy Porea
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme acid beta-glucocerebrosidase (GBA). Deficient hydrolase activity results in the accumulation of glucosylceramide in phagocytes.1 Three variants of GD are reported, with type 1 being the most prevalent with an occurrence of 1:40,000 in the general population.2 Key clinical manifestations of type 1 GD are visceromegaly, hematologic abnormalities, and bone crisis secondary to an inflammatory response of lipid laden macrophage deposition into tissue sites.1 Less common phenotypes types 2 and 3 are defined by the presence of neurologic involvement.3 Diagnosis is confirmed by analysis of glucocerebrosidase activity in peripheral leukocytes and sequencing of the GBA gene.4
An overview of tolerogenic immunotherapies based on plant-made antigens
Published in Expert Opinion on Biological Therapy, 2019
Dania O. Govea-Alonso, Jaime I. Arevalo-Villalobos, Verónica A. Márquez-Escobar, Sornkanok Vimolmangkang, Sergio Rosales-Mendoza
Although the use of a plant-based vaccines in humans has not been approved so far, several prototypes with high potential have been developed. In parallel, the approval of one plant-made biopharmaceutical for human use has been achieved: the case of glucocerebrosidase, an enzyme used as a replacement in Gaucher’s disease, which is produced in carrot cells as an efficient glycoform that does not require expensive in vitro treatment as the homologue produced in mammalian cells [110]. Interestingly, current research is focused in studying the oral delivery of glucocerebrosidase in a clinical phase II trial (www.protalix.com). The results showed that patients with Gaucher’s disease have glucocerebrosidase levels similar to healthy control subjects when consuming a juice-containing carrot cells with glucocerebrosidase [111]. Another highlighted achievement in this field includes the case of ZMapp™, a monoclonal antibodies cocktail to treat Ebola produced in N. benthamiana, which was emergently used to treat seven patients during the 2014 Ebola outbreak based on its efficacy in rhesus macaques [112]. A subsequent clinical trial was conducted in the United States, Liberia, Sierra Leone, and Guinea for ZMapp™ to assess its safety and efficacy. Moreover, other antibodies against infectious agents (e.g. anthrax, respiratory syncytial virus, West Nile virus, and human immunodeficiency virus) and non-Hodgkin’s lymphoma are under evaluation. This relevant topic is reviewed elsewhere [113].