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Genetica e scienze omiche/modelli sperimentali/trasduzione del segnale

Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured renal tubular cells from patients with Fabry disease

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Razionale

We recently demonstrated in fibroblast cell lines of Fabry Disease (FD) patients a synergistic effect between Enzyme Replacement Therapy (ERT) and Pharmacological Chaperone Therapy (PCT). However, although easy to obtain and to manipulate in cultures, the fibroblasts are not the preferred target of therapy in FD.

Therefore, the aim of our study was to test the combination of recombinant human alpha-galactosidase A (rh-alpha-Gal A) with the chaperone molecule 1-deoxynojirimycin (DGJ) in cultured renal tubular cells of FD patients.

Casistica e Metodi

To study the effect of the DGJ on rh-alpha-Gal A efficacy, the tubular cells of 3 FD patients, derived from renal biopsies, were incubated with 5 nmol/l rh-alpha-Gal A for 24 h, in the absence or in the presence of 20 μmol/l DGJ. Untreated cells or cells incubated with DGJ alone were used for comparison. 

Risultati

None of the cell lines showed significant increases in alpha-Gal A activity when incubated with the chaperone alone. The correction of enzyme activity in the cells incubated with the recombinant enzyme alone ranged from 267,41 to 314,37 nmoles 4-methylumbelliferone/mg protein/hour. When the cells where co-incubated with DGJ and rh-alpha-Gal A the intracellular activity increased from 3,26 to 5,08-fold, compared to cells incubated with rh-alpha-Gal A alone. 

Conclusioni

Co-administration of DGJ and rh-alpha-Gal A resulted in all tubular cell lines in a substantial increase in the amount of intracellular enzyme compared with cells treated with rh-alpha-Gal A alone, suggesting improved intracellular stability of the enzyme. Moreover, because of none of the cell lines showed significant increases in alpha-Gal A activity when incubated with the chaperone alone, we provided evidence that this effect is directed towards the exogenous recombinant enzyme and not on the endogenous defective enzyme.

A. Pisani, B. Visciano, I. Capuano, E. Riccio
(Cattedra di Nefrologia, Università degli Studi di Napoli Federico II)
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Realizzazione: Tesi S.p.A.

Per assistenza contattare: Lucia Piumetto, Tesi S.p.A.
0172 476301 — lucia.piumetto@gruppotesi.com