ESHG 2009

Aug 10, 20120 likes136 views

This document discusses testing iminosugars and aminocyclitols as pharmacological chaperones for mutated glucocerebrosidase enzymes associated with Gaucher disease. The study found that NN-DNJ, NB-DNJ, and C4Ph increased the activity of mutated enzymes in transfected COS-7 cells, and that NN-DNJ and C10 increased activity in patient fibroblasts. These results support the potential use of chemical chaperones as a therapeutic approach for Gaucher disease, but developing and analyzing new compounds is still needed.

Health & Medicine

CHAPERONE EFFECT OF SEVERAL IMINOSUGARS AND
AMINOCYCLITOLS ON MUTATED GLUCOCEREBROSIDASES: A
POSSIBLE THERAPEUTIC APPROACH FOR GAUCHER DISEASE
Gessamí Sanchez-Olle1, Joana Duque2, Meritxell Egido-Gabas3, Josefina Casas3, Montserrat Lluch2, Amparo Chabas2, Daniel
Grinberg1, Lluïsa Vilageliu1
1
Deprtament de Genètica, Universitat de Barcelona; IBUB; CIBERER;Barcelona, Spain
2
Institut de Bioquímica Clínica, Hospital Clínic; CIBERER; Barcelona, Spain
3
Research Unit on BioActive Molecules (RUBAM), Departament de Química BioMèdica, Instituto de Química Avanzada de Catalunya, CSIC, Barcelona, Spain

ABSTRACT
Gaucher diseasee is an autosomal recessive disorder, characterized by the accumulation of the mononuclear phagocyte system, attributable to
glucocerebrosidase (GBA; EC3.2.1.45). The main consequences are hepatosplenomegaly, skeletal lesions and, sometimes, neurological manifestations. It has
been shown that at sub-inhibitory concentrations, several competitive inhibitors can work as chemical chaperones, by inducing protein stabilization and
increasing enzymatic activity. We have tested two iminosugars (NB-DNJ and NN-DNJ) and four aminocyclitols (C8, C9, C10, C4Ph) with distinct degrees of
lipophilicity as pharmacological chaperones on mutated GBAs. We report an increase in the activity of GBA using NN-DNJ, NB-DNJ and C4Ph in stable
transfected COS-7 cells and an increment with NN-DNJ and C10 in patient fibroblasts.

RESULTS
TRANSFECTED COS-7 CELLS PATIENT FIBROBLASTS
NN-DNJ NN-DNJ

At 2.5µM, NN-DNJ leads to a 1.2 and 1.4-fold increase in the activity
of G377S and N188S GBA, respectively. At 5µM, NN-DNJ leads to a
1.2-fold increase in the activity of wt, N188S and G377S. A slight
increase is noticed in the activity of wt and N188S;E326K GBA at
2.5µM. * p≤0.05.
For the N370S/N370S fibroblasts, a 1.7-fold increase was observed
at 5µM and 10 µM. A 1.5-fold increase was observed at 20µM and,
NB-DNJ still, a 1.3-fold increase at 60µM. For the D409H/N188S;E326K
fibroblasts, the increase was of 1.2 to 1.4-folds, with a maximum for 5
and 10µM. Finally, for the N370S/L444P cells, the increase was in the
1.2 to 1.4-fold range for concentrations between 2.5 to 10µM, being
the maximum at 10µM.

C10

NB-DNJ induces a 1.2-fold increase in the activity of N188S and
N188S;E326K GBA at 5µM.

C4Ph

A 1.7-fold increase was reached for the L444P;E326K/G202R cells, at
At 15µM 1.2-fold increase for N188S and N188S; E326K GBA and a 20 and 30µM, and a 1.5-fold increase for the L444P/G202R
1.3-fold increased for wt GBA are observed. At 20µM 1.3 and 1.4-fold fibroblasts at 25µM.
increase is shown for N188S and wt GBA respectively. * p≤0.05.

CONCLUSION
These promising results on specific mutations validate the use of chemical chaperones as a therapeutic approach for Gaucher disease. However,
the development and analysis of new compounds is required.

As a next step, we are currently analysing the abnormal intracellular trafficking of mutant glucocerebrosidases by immunohistochemical
techniques and confocal microscopy.

High resolution melt analysis (HRM) is an advanced post-PCR technique for analyzing genetic variations by detecting differences in thermal denaturation of double-stranded DNA. It allows for the rapid, cost-effective screening of mutations, including SNP genotyping and DNA methylation analysis, by measuring fluorescence changes associated with melting temperature variations. HRM enhances specificity and sensitivity in various applications, such as species identification and haplotype characterization.

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ESHG 2009

1. CHAPERONE EFFECT OF SEVERAL IMINOSUGARS AND AMINOCYCLITOLS ON MUTATED GLUCOCEREBROSIDASES: A POSSIBLE THERAPEUTIC APPROACH FOR GAUCHER DISEASE Gessamí Sanchez-Olle1, Joana Duque2, Meritxell Egido-Gabas3, Josefina Casas3, Montserrat Lluch2, Amparo Chabas2, Daniel Grinberg1, Lluïsa Vilageliu1 1 Deprtament de Genètica, Universitat de Barcelona; IBUB; CIBERER;Barcelona, Spain 2 Institut de Bioquímica Clínica, Hospital Clínic; CIBERER; Barcelona, Spain 3 Research Unit on BioActive Molecules (RUBAM), Departament de Química BioMèdica, Instituto de Química Avanzada de Catalunya, CSIC, Barcelona, Spain ABSTRACT Gaucher diseasee is an autosomal recessive disorder, characterized by the accumulation of the mononuclear phagocyte system, attributable to glucocerebrosidase (GBA; EC3.2.1.45). The main consequences are hepatosplenomegaly, skeletal lesions and, sometimes, neurological manifestations. It has been shown that at sub-inhibitory concentrations, several competitive inhibitors can work as chemical chaperones, by inducing protein stabilization and increasing enzymatic activity. We have tested two iminosugars (NB-DNJ and NN-DNJ) and four aminocyclitols (C8, C9, C10, C4Ph) with distinct degrees of lipophilicity as pharmacological chaperones on mutated GBAs. We report an increase in the activity of GBA using NN-DNJ, NB-DNJ and C4Ph in stable transfected COS-7 cells and an increment with NN-DNJ and C10 in patient fibroblasts. RESULTS TRANSFECTED COS-7 CELLS PATIENT FIBROBLASTS NN-DNJ NN-DNJ At 2.5µM, NN-DNJ leads to a 1.2 and 1.4-fold increase in the activity of G377S and N188S GBA, respectively. At 5µM, NN-DNJ leads to a 1.2-fold increase in the activity of wt, N188S and G377S. A slight increase is noticed in the activity of wt and N188S;E326K GBA at 2.5µM. * p≤0.05. For the N370S/N370S fibroblasts, a 1.7-fold increase was observed at 5µM and 10 µM. A 1.5-fold increase was observed at 20µM and, NB-DNJ still, a 1.3-fold increase at 60µM. For the D409H/N188S;E326K fibroblasts, the increase was of 1.2 to 1.4-folds, with a maximum for 5 and 10µM. Finally, for the N370S/L444P cells, the increase was in the 1.2 to 1.4-fold range for concentrations between 2.5 to 10µM, being the maximum at 10µM. C10 NB-DNJ induces a 1.2-fold increase in the activity of N188S and N188S;E326K GBA at 5µM. C4Ph A 1.7-fold increase was reached for the L444P;E326K/G202R cells, at At 15µM 1.2-fold increase for N188S and N188S; E326K GBA and a 20 and 30µM, and a 1.5-fold increase for the L444P/G202R 1.3-fold increased for wt GBA are observed. At 20µM 1.3 and 1.4-fold fibroblasts at 25µM. increase is shown for N188S and wt GBA respectively. * p≤0.05. CONCLUSION These promising results on specific mutations validate the use of chemical chaperones as a therapeutic approach for Gaucher disease. However, the development and analysis of new compounds is required. As a next step, we are currently analysing the abnormal intracellular trafficking of mutant glucocerebrosidases by immunohistochemical techniques and confocal microscopy.

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ESHG 2009

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