Academic Journal
Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies
| العنوان: | Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
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| المؤلفون: | Germain Dominique P, Giugliani Roberto, Hughes Derralynn A, Mehta Atul, Nicholls Kathy, Barisoni Laura, Jennette Charles J, Bragat Alexander, Castelli Jeff, Sitaraman Sheela, Lockhart David J, Boudes Pol F |
| المصدر: | Orphanet Journal of Rare Diseases, Vol 7, Iss 1, p 91 (2012) |
| بيانات النشر: | BMC |
| سنة النشر: | 2012 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Pharmacological chaperone, Conformational diseases, Protein-misfolding, Fabry disease, Lysosomal storage disorder, Medicine |
| الوصف: | Background Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. Methods Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Results Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. Conclusions Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. Trial registration Clinicaltrial.gov: NCT00283959 and NCT00283933 |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1750-1172 |
| Relation: | http://www.ojrd.com/content/7/1/91; https://doaj.org/toc/1750-1172; https://doaj.org/article/551598c86aad4df1b5dfe657d878b939 |
| DOI: | 10.1186/1750-1172-7-91 |
| الاتاحة: | https://doi.org/10.1186/1750-1172-7-91 https://doaj.org/article/551598c86aad4df1b5dfe657d878b939 |
| رقم الانضمام: | edsbas.21BD4555 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 17501172 |
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| DOI: | 10.1186/1750-1172-7-91 |