http://www.cnr.it/ontology/cnr/individuo/prodotto/ID16241
Therapy of Fabry disease with pharmacological chaperones: from in silico predictions to in vitro tests (Articolo in rivista)
- Type
- Label
- Therapy of Fabry disease with pharmacological chaperones: from in silico predictions to in vitro tests (Articolo in rivista) (literal)
- Anno
- 2011-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1186/1750-1172-6-66 (literal)
- Alternative label
G. Andreotti, V. Citro, A. De Crescenzo, P. Orlando, M. Cammisa, A. Correra and M.V. Cubellis (2011)
Therapy of Fabry disease with pharmacological chaperones: from in silico predictions to in vitro tests
in Orphanet journal of rare diseases
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- G. Andreotti, V. Citro, A. De Crescenzo, P. Orlando, M. Cammisa, A. Correra and M.V. Cubellis (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
- http://www.ojrd.com/content/6/1/66 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
- Rivista
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#note
- doi:10.1186/1750-1172-6-66 (literal)
- Note
- ISI Web of Science (WOS) (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- Andreotti Giuseppina, Istituto di Chimica Biomolecolare - CNR, Pozzuoli, Italy
Citro Valentina, Institute of Genetics and Biophysics 'A. Buzzati Traverso,' CNR, Naples, Italy
De Crescenzo Agostina, Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Caserta, Italy
Orlando Pierangelo, Institute of Protein Biochemistry-CNR, Napoli, Italy
Cubellis Maria Vittoria, Cammisa Marco, Correra Antonella, Dipartimento di Biologia Strutturale e Funzionale, Università Federico II, Napoli, Italy and Istituto di Biostrutture e Bioimmagini-CNR, Napoli, Italy (literal)
- Titolo
- Therapy of Fabry disease with pharmacological chaperones: from in silico predictions to in vitro tests (literal)
- Abstract
- Background: Fabry disease is a rare disorder caused by a large variety of mutations in the gene encoding
lysosomal alpha-galactosidase. Many of these mutations are unique to individual families. Fabry disease can be
treated with enzyme replacement therapy, but a promising novel strategy relies on small molecules, so called
\"pharmacological chaperones\", which can be administered orally. Unfortunately only 42% of genotypes respond to
pharmacological chaperones.
Results: A procedure to predict which genotypes responsive to pharmacological chaperones in Fabry disease has been
recently proposed. The method uses a position-specific substitution matrix to score the mutations. Using this method,
we have screened public databases for predictable responsive cases and selected nine representative mutations as yet
untested with pharmacological chaperones. Mutant lysosomal alpha galactosidases were produced by site directed
mutagenesis and expressed in mammalian cells. Seven out of nine mutations responded to pharmacological
chaperones. Nineteen other mutations that were tested with pharmacological chaperones, but were not included in
the training of the predictive method, were gathered from literature and analyzed in silico. In this set all five mutations
predicted to be positive were responsive to pharmacological chaperones, bringing the percentage of responsive
mutations among those predicted to be positive and not used to train the classifier to 86% (12/14). This figure differs
significantly from the percentage of responsive cases observed among all the Fabry mutants tested so far.
Conclusions: In this paper we provide experimental support to an \"in silico\" method designed to predict missense
mutations in the gene encoding lysosomal alpha galactosidase responsive to pharmacological chaperones. We
demonstrated that responsive mutations can be predicted with a low percentage of false positive cases. Most of
the mutations tested to validate the method were described in the literature as associated to classic or mild classic
phenotype. The analysis can provide a guideline for the therapy with pharmacological chaperones supported by
experimental results obtained in vitro. We are aware that our results were obtained in vitro and cannot be
translated straightforwardly into benefit for patients, but need to be validated by clinical trials. (literal)
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