Scientists Shed Light on Potential Treatment for Gaucher’s Disease

University of Pittsburgh researchers reported promising results in mice with a potential "gene therapy" for Gaucher's disease that eventually may replace Ceredase, a Genzyme Corp. drug whose high cost has sparked controversy. The study indicated it would be possible to transfer a gene into certain cells of people with the disease that would permanently correct a genetic defect underlying their disorder. The potential treatment, however, is at least several years away from widespread use in patients, and its development may face economic stumbling blocks.

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758 Convection-enhanced Delivery of Glucocerebrosidase to the Primate Brain as a Potential Treatment for Neuronopathic Gaucher's Disease

Neurosurgery ◽

10.1227/00006123-200408000-00094 ◽

2004 ◽

Vol 55 (2) ◽

pp. 471-472

Author(s):

Michele Aizenberg ◽

Stuart Walbridge ◽

Murray J. Gary ◽

Alexander O. Vortmeyer ◽

Roscoe O. Brady ◽

...

Keyword(s):

Potential Treatment ◽

Convection Enhanced Delivery ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Primate Brain

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Future perspectives for glycolipid research in medicine

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2003.1270 ◽

2003 ◽

Vol 358 (1433) ◽

pp. 967-973 ◽

Cited By ~ 10

Author(s):

Timothy M. Cox

Keyword(s):

Clinical Trials ◽

Cancer Biology ◽

Substrate Reduction Therapy ◽

Definitive Treatment ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Substrate Reduction ◽

Shed Light ◽

Storage Disorders

Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1–phosphate). Other sphingolipid metabolites such as ceramide 1–phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage–targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar N –butyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.

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Functional read out of defective osteoclast function in an in vitro model of Gaucher's disease

Endocrine Abstracts ◽

10.1530/endoabs.34.p26 ◽

2014 ◽

Author(s):

Sarbjit Nijjar ◽

Neil Gittoes ◽

Tarekegn Geberhiwot

Keyword(s):

In Vitro Model ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Vitro Model ◽

Osteoclast Function

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Sudden death due to undiagnosed Gaucher's disease: Case report and revue of the literature

10.26226/morressier.578f37fbd462b8028d890126 ◽

2016 ◽

Author(s):

Youssef Chkirbene

Keyword(s):

Case Report ◽

Sudden Death ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Disease Case

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Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)

Molecular Brain ◽

10.1186/s13041-021-00790-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Etsuro Nakanishi ◽

Norihito Uemura ◽

Hisako Akiyama ◽

Masato Kinoshita ◽

Sawamura Masanori ◽

...

Keyword(s):

Microglial Activation ◽

Biochemical Analysis ◽

Neuronal Cell ◽

Cell Loss ◽

Pathological Changes ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Short Lifespan ◽

Behavioral Abnormalities ◽

Glucocerebrosidase Gene

AbstractHomozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher’s disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson’s disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that deletion of GBA2, non-lysosomal glucocerebrosidase, in a non-neuronopathic GD mouse model rescued its phenotypes. In the present study, we generated gba2 KO medaka and examined the effect of Gba2 deletion on the phenotypes of gba1 KO medaka. The Gba2 deletion in gba1 KO medaka resulted in the exacerbation of glucosylceramide accumulation and no improvement in neuronopathic GD pathological changes, asyn accumulation, or swimming abnormalities. Meanwhile, though gba2 KO medaka did not show any apparent phenotypes, biochemical analysis revealed asyn accumulation in the brains. gba2 KO medaka showed a trend towards an increase in sphingolipids in the brains, which is one of the possible causes of asyn accumulation. In conclusion, this study demonstrated that the deletion of Gba2 does not rescue the pathological changes or behavioral abnormalities of gba1 KO medaka, and GBA2 represents a novel factor affecting asyn accumulation in the brains.

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