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1.
J Pharmacol Exp Ther ; 387(2): 188-203, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37679046

RESUMEN

Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid α-glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid α-glucosidase, was the first approved treatment of Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease. This recently approved enzyme replacement therapy (ERT) was glycoengineered to maximize CIMPR binding through high-affinity interactions with ∼7 bis-M6P moieties. Recently, small molecules like the glucosylceramide synthase inhibitor miglustat were reported to increase the stability of recombinant human acid α-glucosidase, and it was suggested that an increased serum half-life would result in better glycogen clearance. Here, the effects of miglustat on alglucosidase alfa and avalglucosidase alfa stability, activity, and efficacy in Pompe mice were evaluated. Although miglustat increased the stability of both enzymes in fluorescent protein thermal shift assays and when incubated in neutral pH buffer over time, it reduced their enzymatic activity by ∼50%. Improvement in tissue glycogen clearance and transcriptional dysregulation in Pompe mice correlated with M6P levels but not with miglustat coadministration. These results further substantiate the crucial role of CIMPR binding in lysosomal targeting of ERTs. SIGNIFICANCE STATEMENT: This work describes important new insights into the treatment of Pompe disease using currently approved enzyme replacement therapies (ERTs) coadministered with miglustat. Although miglustat increased the stability of ERTs in vitro, there was no positive impact to glycogen clearance and transcriptional correction in Pompe mice. However, increasing mannose-6-phosphate levels resulted in increased cell uptake in vitro and increased glycogen clearance and transcriptional correction in Pompe mice, further underscoring the crucial role of cation-independent mannose-6-phosphate receptor-mediated lysosomal targeting for ERTs.

2.
J Chromatogr B Analyt Technol Biomed Life Sci ; 846(1-2): 245-51, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17011839

RESUMEN

An ion exchange high performance liquid chromatography method was developed for determining creatinine levels in both mouse and rat serum samples. Separation of creatinine from other serum components was achieved in 10 min using a 100 x 4.1-mm, 10 microm strong cation exchange column following acetonitrile precipitation of serum proteins. Incorporation of a guard cartridge placed in-line prior to the analytical column was employed to prevent interference from compounds used in renal disease animal trials. Creatinine levels in normal and diseased animals were accurately determined in the 0.01-10 mg/dL range, and average recovery of the method was approximately 85% for both mouse and rat serum. Addition of 0.5-1.0% acetic acid to the acetonitrile used for protein precipitation significantly improved creatinine recovery to above 97% in mouse serum. The method was used for routine preclinical diagnosis of rat and mouse model renal function, and for the evaluation of renal disease treatment efficacy.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cromatografía por Intercambio Iónico/métodos , Creatinina/sangre , Pruebas de Función Renal , Animales , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratas , Reproducibilidad de los Resultados
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