Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy

Kelo, Eira; Dunder, Ulla; Mononen, Ilkka

doi:10.1093/glycob/cwh145

Cited by 17 publications

(14 citation statements)

References 24 publications

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“…Already in the 1990’s, bone marrow transplantation (BMT) was carried out with some patients, but the therapeutic effect remained very benign as compared to the side effects of BMT2324. In addition, the two existing AGU mouse models2526 have been subjected to therapy trials using ERT or gene therapy10111213, but these studies have so far not led to clinical trials with patients, despite their beneficial effects. ERT as a potential AGU therapy has been hampered by difficulties to produce sufficient amounts of recombinant AGA enzyme for therapy of human patients.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Banning

Gülec

Rouvinen

et al. 2016

Sci Rep

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Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU.

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Section: Discussionmentioning

confidence: 99%

“…Currently, no treatment for AGU is available, although several preclinical studies aiming at enzyme replacement (ERT)1011 or gene therapy1213 have been published. Neither of these treatment options is expected to be available within the next few years, and there is thus a vast demand for an alternative therapy for AGU.…”

mentioning

confidence: 99%

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Banning

Gülec

Rouvinen

et al. 2016

Sci Rep

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“…The response to therapy was dose-dependent: the higher the glycosylasparaginase dose the faster the clearance of aspartylglucosamine [62]. Massive accumulation of a larger glycoasparagine (Man2GlcNAc-Asn) in tissues of AGU mice was also effectively corrected with glycosylasparaginase replacement therapy [63]. …”

Section: Experimental Therapymentioning

confidence: 99%

Aspartylglycosaminuria: a review

Arvio

Mononen

2016

Orphanet J Rare Dis

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Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the Finnish population. It is a lifelong condition affecting on the patient’s appearance, cognition, adaptive skills, physical growth, personality, body structure, and health. An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU. Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50 years.The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA), which leads to a disorder in the degradation of glycoasparagines – aspartylglucosamine or other glycoconjugates with an aspartylglucosamine moiety at their reducing end – and accumulation of these undegraded glycoasparagines in tissues and body fluids. A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population. Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population. A mouse strain, which completely lacks the Aga activity has been generated through targeted disruption of the Aga gene in embryonic stem cells. These Aga-deficient mice share most of the clinical, histopathologic and biochemical characteristics of human AGU disease. Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals. The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol. Enzyme replacement trials on human AGU patients have not been reported so far. Allogenic stem cell transplantation has not proved effective in curing AGU.

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“…54 In adenovirus-mediated gene therapy trials using 2 two tissue-specific promoters and the endogenous promoter in the AGU knockout mouse, AGA expression was increased and storage markedly decreased in some cases. 55 …”

Section: Therapymentioning

confidence: 99%

Disorders of Glycoprotein Degradation

Johnson¹

2015

Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease

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Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy

Cited by 17 publications

References 24 publications

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria

Aspartylglycosaminuria: a review

Disorders of Glycoprotein Degradation

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