Migalastat HCl reduces globotriaosylsphingosine (Lyso- Gb3) in Fabry transgenic mice and in the plasma of Fabry patients

• Autor(a) principal: Young-Gqamana, Brandy
• Data de Publicação: 2013
• Outros Autores: Brignol, N., Chang, Hui-Hwa, Khanna, R., Soska, R., Fuller, Maria, Sitaraman, Sheela, Germain, Dominique P., Giugliani, Roberto, Hughes, Derralynn A., Mehta, Atul B., Nicholls, Kathy, Boudes, Pol F., Lockhart, D.J., Valenzano, K.J., Benjamin, Elfrida R.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/200305
• topic: Camundongos transgênicos; Doença de Fabry

Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme a-galactosidase A (a-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of a-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3 in mouse tissues and human plasma. Oral administration of migalastat HCl to transgenic mice reduced elevated lyso-Gb3 levels up to 64%, 59%, and 81% in kidney, heart, and skin, respectively, generally equal to or greater than observed for GL-3. Furthermore, baseline plasma lyso-Gb3 levels were markedly elevated in six male FD patients enrolled in Phase 2 studies. Oral administration of migalastat HCl (150 mg QOD) reduced urine GL-3 and plasma lyso-Gb3 in three subjects (range: 15% to 46% within 48 weeks of treatment). In contrast, three showed no reductions in either substrate. These results suggest that measurement of tissue and/or plasma lyso-Gb3 is feasible and may be warranted in future studies of migalastat HCl or other new potential therapies for FD.