scholarly journals Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease

2016 ◽  
Vol 24 (12) ◽  
pp. 2054-2063 ◽  
Author(s):  
Marialuisa Alliegro ◽  
Rita Ferla ◽  
Edoardo Nusco ◽  
Chiara De Leonibus ◽  
Carmine Settembre ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage Disease ◽  
Low Dose ◽  
Storage Disease ◽  
Lysosomal Storage ◽  
Enzyme Replacement

scholarly journals Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency

2020 ◽  
Vol 295 (39) ◽  
pp. 13556-13569 ◽  
Author(s):  
Amanda R. Luu ◽  
Cara Wong ◽  
Vishal Agrawal ◽  
Nathan Wise ◽  
Britta Handyside ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Activity Levels ◽  
Multienzyme Complex ◽  
Lysosomal Storage ◽  
Gm1 Gangliosidosis ◽  
Enzyme Replacement ◽  
Clinical Onset

Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, β-Gal only partially depends on PPCA, prompting us to investigate the role that β-Gal plays in the multienzyme complex. Here, we demonstrate that β-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human β-Gal (rhβ-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhβ-Gal, followed by enzyme withdrawal, is sufficient to augment β-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of β-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhβ-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of β-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhβ-Gal is a tunable approach that can safely augment β-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.

scholarly journals Gasser cell: A biomarker of response to enzyme replacement therapy in patients with mucopolysaccharidosis type VI

2021 ◽  
Vol 10 (5) ◽  
pp. e24510514726
Author(s):  
Márcio Antonio Wanderley de Melo ◽  
Marcelo Soares Kertenetzky ◽  
Cristina Magalhães da Silveira ◽  
Maíra Magalhães Ribeiro ◽  
Gabriela da Silva Arcanjo ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Storage Disease ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mucopolysaccharidosis Type Vi ◽  
Cell Counts ◽  
Before And After ◽  
Complete Cell

The mucopolysaccharidosis (MPS) type VI is a rare lysosomal storage disease presenting leukocyte inclusions (Alder-Reilly anomaly) and lymphocytes with metachromatic inclusion surrounded by clear spaces, Gasser cells. Currently, an enzyme replacement therapy (ERT) with galsulfase is used to treat MPS type VI. This study evaluated 14 patients with MPS type VI performed cell counts Gasser before and after six months from the beginning of ERT. It was observed an average of 12.7% cells per patient, and after six months was found complete cell Gasser disappearance, proving to be an effective biomarker of response to ERT.

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