Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002986 (Fabry)
 5,646 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fabry disease is caused by the deficiency of lysosomal alpha-galactosidase A (alpha-gal A) and usually develops clinical manifestations during childhood/adolescence. Adult Fabry model mice have been successfully treated by various viral vectors. Here, in order to examine the feasibility of preventive gene therapy, we compared AAV vector-mediated gene transfer into neonatal and adult model mice. AAV serotype 1 vector (AAV1) carrying human alpha-gal A cDNA driven by the CAG promoter was intravenously injected into adult (12 weeks old) and neonatal (2 days old) Fabry model mice, and were sacrificed for detailed examination 25 weeks after vector injection. AAV1 vector preferentially transduced the liver in male adult and sustained high concentration of alpha-gal A was detected in the liver, heart and plasma. In contrast, AAV1-mediated gene expression was suppressed in similarly treated female adult mice. When the vector was systemically injected into neonates, moderate increase in plasma alpha-gal A and cardiac-specific expression of alpha-gal A were observed independently of mouse sex. The high levels of alpha-gal A activity in the heart appear to be due to the strong activity of the CAG promoter in the heart. Globotriaosylceramide (Gb3) accumulation was efficiently inhibited in the liver and heart by a single injection into both adult and neonatal animals. The biodistribution of the AAV1 vector and levels of alpha-gal A expression are markedly different between adult and neonatal mice. Neonatal injection is effective to inhibit Gb3 accumulation and therefore, might help prevent failure of major organs during adulthood.
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PMID:Long-term inhibition of glycosphingolipid accumulation in Fabry model mice by a single systemic injection of AAV1 vector in the neonatal period. 1908 54

Fabry disease is an inborn error of glycosphingolipid metabolism caused by deficiency of alpha-galactosidase A (alpha-Gal A) activity. It has been shown that protein misfolding is primarily responsible for the enzyme deficiency in a large proportion of mutations identified in Fabry patients with residual enzyme activity, and 1-deoxygalactonojirimycin (DGJ) can effectively increase the residual enzyme activity in cultured patient's cells. Herein, we demonstrate the preclinical efficacy and safety of DGJ in transgenic mice that express human mutant alpha-Gal A activity. alpha-Gal A activity in heart, kidney, spleen, and liver was increased dose- and time-dependently. The mutant alpha-Gal A was increased in cardiomyocytes and distal convoluted tubules of the transgenic mice in a null background after 2 weeks of DGJ treatment. Globotriaosylceramide storage was remarkably reduced in kidney of mice after a 4-week treatment at a dosage of approximately 3 mg/kg body weight/day. The half-life of DGJ was less than 1 day in all major issues and that of the enzyme synthesized during the DGJ treatment period was approximately 4 days. No abnormality of blood chemistry and pathological tissue damage was found in mice treated with DGJ at approximately 30 mg/kg body weight/day for 9 weeks. Furthermore, no change was observed in appearance, growth, fertility, and life span in mice during a 2-year period of continuous administration of DGJ at the effective dosage. These preclinical results indicate that DGJ is effective in restoring mutant enzyme activity in tissues and reversing substrate storage in kidney and is well tolerated in mice.
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PMID:Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. 1910 70

Thomaidis and colleagues have created a cellular model of Anderson-Fabry disease by 'silencing' alpha-galactosidase A (AGAL) activity in human tubular epithelial cells. Increased membrane globotriaosylceramide (Gb3/CD77) expression was observed; it is suggested that this finding may be potentially useful as a surrogate marker of disease severity. Decreased membrane Gb3/CD77 expression was observed following agalsidase-alpha treatment, providing evidence of changes in cellular phenotype in response to enzyme therapy.
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PMID:To see a world in a grain of sand: elucidating the pathophysiology of Anderson-Fabry disease through investigations of a cellular model. 1903 53

The lysosomal storage disorder Fabry disease is characterized by excessive globotriaosylceramide (Gb3) accumulation in major organs such as the heart and kidney. Defective lysosomal alpha-galactosidase A (Gla) is responsible for excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3 accumulation is vascular endothelium. Endothelial dysfunction is associated with Fabry disease and excessive cellular Gb3. We previously demonstrated that excessive vascular Gb3 in a mouse model of Fabry disease, the Gla-knockout (Gla(-/0)) mouse, results in abnormal vascular function, which includes abnormal endothelium-dependent contractions, a vascular phenomenon known to involve cyclooxygenase (COX). Therefore, we hypothesized that the vasculopathy in the Gla knockout mouse may be due to a vasoactive COX-derived product. To test this hypothesis, vascular reactivity experiments were performed in aortic rings from wild-type (Gla(+/0)) and Gla(-/0) mice in the presence and absence of specific and nonspecific COX inhibitors. Specific inhibition of COX1 or COX2 in endothelium-intact rings from Gla(-/0) mice decreased overall phenylephrine contractility compared with untreated Gla(-/0) rings, whereas COX inhibitors had no effect on contractility in endothelium-denuded rings. Nonspecific inhibition of COX with indomethacin (10 micromol/l) or COX1 inhibition with valeryl salicylate (3 mmol/l) improved endothelial function in rings from Gla(-/0) mice, but COX2 inhibition with NS-398 (1 micromol/l) further increased endothelial dysfunction in rings from Gla(-/0) mice. These results suggest that, in the Gla(-/0) mice, COX1 and COX2 activity are increased and localized in the endothelium, producing vasopressor and vasorelaxant products, which contribute to the Fabry-related vasculopathy.
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PMID:Differential involvement of COX1 and COX2 in the vasculopathy associated with the alpha-galactosidase A-knockout mouse. 1920

Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, alpha-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease.
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PMID:Fabry disease in children and the effects of enzyme replacement treatment. 1924 21

There are no data regarding changes in plasma brain natriuretic peptide (BNP) levels in patients with Fabry's diseases during enzyme replacement therapy (ERT). We describe a patient with Fabry's disease who demonstrated the improvement in plasma brain BNP levels in response to ERT. Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A, which results in progressive intracellular accumulation of globotriaosylceramide (Gb3) in various organs including the heart. Cardiac involvement is frequent in Fabry's disease, resulting in cardiac dysfunction due to hypertrophic changes of the myocardium and thickening of the valves. Although ERT has been reported to improve cardiac function, no consensus has been reached regarding the effectiveness of ERT in female patients with heterozygous Fabry's disease. We report a 44-year-old woman having heterozygous Fabry's disease, who showed mitral valve thickening and regurgitation on echocardiogram. ERT was performed by intravenous infusion of recombinant alpha-galactosidase A every 2 weeks. We assessed the influences of ERT on cardiac function by measuring echocardiograhic parameters and monitoring BNP levels, which show treatment-induced drop in patients with heart failure. Although her cardiac function and mitral regurgitation assessed by echocardiography had not improved 18 months after the beginning of ERT, the plasma BNP level, which was 91.5 pg/ml before ERT, fell to 18.9 pg/ml. In conclusion, plasma BNP levels may be useful for evaluating the effectiveness of ERT for heterozygous Fabry's disease, even in patients who demonstrate no improvement in echocardiographic parameters of cardiac structure and function.
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PMID:Decline of plasma brain natriuretic peptide during enzyme replacement therapy in a female patient with heterozygous Fabry's disease. 1928 51

Fabry disease is a lysosomal storage disease caused by a deficiency of alpha-galactosidase A, which results in aberrant glycosphingolipid metabolism and accumulation of globotriaosylceramide (Gb3). Since a correlation between the level of Gb3 and clinical manifestations of Fabry disease has not been observed, we investigated potential diagnostic biomarkers. Hepatic and renal gene expression of male alpha-galactosidase A-deficient mice (Fabry mice) was compared with that of wild-type mice. Microarray analyses were performed using samples taken before and after intravenous infusion of alpha-galactosidase A. The identified genes were validated using quantitative real-time PCR and Western blot assay. Expression of hepatic Serum Amyloid A1 (Saa1), S100 Calcium-binding protein A8 and A9 (S100a8 and a9), and Lipocalin 2 (Lcn2) and renal Neuropeptide Y (Npy), Thrombospondin 2 and 4 (Tsp-2 and -4) was significantly upregulated in Fabry mice compared with wild-type mice and normalized by enzyme replacement therapy. Plasma concentrations of Lcn2 and Npy were also greater in Fabry mice and reduced to wild-type levels after enzyme replacement therapy, although the plasma concentrations of these proteins show heterogeneity. Upregulation of Saa1, S100a8, S100a9 and Lcn2 may modulate inflammation and Lcn2, Npy and Tsp may be associated with vascular and renal involvement in Fabry disease. Furthermore, these genes are promising targets for developing biomarkers for monitoring disease progression and therapeutic efficacy in patients with Fabry disease.
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PMID:Expression of genes and their responses to enzyme replacement therapy in a Fabry disease mouse model. 1963 34

Abnormal biosynthesis of globotriaosylceramide (Gb3) is known to be associated with Gb3-related diseases, such as Fabry disease. The Gb3 synthase gene (Gb3S) codes for alpha1,4-galactosyltransferase, which is a key enzyme involved in Gb3 biosynthesis in vivo. Transcriptional repression of Gb3S is a way to control Gb3 biosynthesis and may be a suitable target for the treatment of Gb3-related diseases. To find a transcriptional inhibitor for Gb3S, we developed a convenient cell-based chemical screening assay system by constructing a fusion gene construct of the human Gb3S promoter and a secreted luciferase as reporter. Using this assay, we identified 2-deoxy-D-glucose as a potent inhibitor for the Gb3S promoter. In cultured cells, 2-deoxy-D-glucose markedly reduced endogenous Gb3S mRNA levels, resulting in a reduction in cellular Gb3 content and a corresponding accumulation of the precursor lactosylceramide. Moreover, cytokine-induced expression of Gb3 on the cell surface of endothelial cells, which is closely related to the onset of hemolytic uremic syndrome in O157-infected patients, was also suppressed by 2-deoxy-D-glucose treatment. These results indicate that 2-deoxy-D-glucose can control Gb3 biosynthesis through the inhibition of Gb3S transcription. Furthermore, we demonstrated the general utility of our novel screening assay for the identification of new inhibitors of glycosphingolipid biosynthesis.
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PMID:A novel, promoter-based, target-specific assay identifies 2-deoxy-D-glucose as an inhibitor of globotriaosylceramide biosynthesis. 1967 1

Anderson-Fabry disease (AFD) is an X-linked storage disorder caused by a deficiency of the lysosomal hydrolase a-galactosidase A (AGAL) and the resultant accumulation of its glycosphingolipid substrate (Gb3) in several tissue types. Major morbidity and reduced life expectancy among affected individuals are a consequence of renal, cardiac and cerebrovascular involvement. Symptomatic males and females with AFD have been described, although the onset of clinical manifestations may be delayed and more variable among the latter patient group, partly attributed to lyonization. Agalsidase alfa (Replagal()) is a recombinant formulation of human AGAL which has been demonstrated to modify the course of AFD in treated patients. Factors that may influence clinical outcomes include disease stage at the point of treatment initiation and antibody formation. There is incomplete understanding of AFD pathophysiology. Early diagnosis and timely intervention may be essential. The use of adjunctive therapies, directed at risk reduction (eg, aspirin for stroke prophylaxis), require careful scrutiny, but such agents are likely to be vital components of a comprehensive approach to patient care. Long-term studies may clarify the optimal dose and frequency of enzyme administration. Meanwhile, budding strategies such as chaperone-mediated enzyme enhancement may offer the potential for an alternative or multimodality approach to the management of AFD.
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PMID:Agalsidase alfa (Replagal) in the treatment of Anderson-Fabry disease. 1970 38

Fabry's disease is an inherited lysosomal storage disorder characterized by the lack of enzyme alpha-galactosidase A (alpha-Gal A) which degrades globotriaosylceramides (Gb3) into products with lower molecular weight. The accumulation of Gb3 in different cell types is responsible for the variety of clinical manifestations. The renal function, estimated via proteinuria, hematuria and reduction of glomerular filtration rate (GRF), is heavily affected. Currently, substitution of alpha-Gal A remains the only therapeutic option for patients with Fabry's disease. Two products are approved for the treatment of Fabry's disease: agalsidase alfa and agalsidase beta. Both of these enzymes have shown a stabilization of renal function in various studies when evaluated by the creatinine clearance, estimated GFR, and serum creatinine. The pro gnosis has proven to be significantly better in cases of mild or moderate renal insufficiency from the baseline. For this reason, an early substitution of the lacking enzyme is necessary. Furthermore, enzyme replacement therapy (ERT) has proven efficient in reducing the amount of intracellular Gb3 and Gb3 in urine. Without treatment, an eGFR reduction of approximately 12 ml/min/year has been reported. After diverse studies of ERT, no significant correlation between enzyme substitution and improvement of patients' proteinuria could be shown. Furthermore, renoprotective drugs have not been consistently applied so far in the ERT trials. In any case, further studies to evaluate the long-term effect of ERT on the morbidity and mortality of patients with Fabry's disease are necessary.
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PMID:[Effect of enzyme replacement therapy (ERT) on renal function of patients with Fabry's disease]. 1977 74


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