I know everyone is sick to death of hearing this may be it, but this is a very positive step and it is a drug already approved by the FDA to treat another orphan illness. Don't shoot the messenger!!! It is moving very quickly and is already in phase IIa trials in Spain. And, Preston Campbell held it in his hand at a recent event as an oral drug to treat the delta f508 mutation.
1: J Pharmacol Exp Ther. 2008 Feb 28 [Epub ahead of print] Links
PARALLEL IMPROVEMENT OF SODIUM AND CHLORIDE TRANSPORT DEFECTS BY MIGLUSTAT IN CYSTIC FIBROSIS EPITHELIAL CELLS.
Noel S, Wilke M, Bot A, De Jonge H, Becq F.
IPBC CNRS UMR 6187.
Cystic Fibrosis, an autosomal recessive disease frequently diagnosed in the Caucasian population, is characterized by deficient Cl(-) transport due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A second major hallmark of the disease is Na(+) hyperabsorption by the airways, mediated by the epithelial Na(+) channel (ENaC). Here we report that in human airway epithelial CF15 cells treated with the CFTR corrector miglustat, whole-cell patch-clamp experiments showed reduced amiloride-sensitive ENaC current in parallel with a rescue of defective CFTR Cl(-) channel activity activated by forskolin and genistein. Similar results were obtained with cells maintained in culture at 27( degrees )C for 24h prior to electrophysiology experiments. With monolayers of polarized CF15 cells, short-circuit current (Isc) measurements also show normalization of Na(+) and Cl(-) currents.<b> In excised nasal epithelium of cftr(F508del/F508del) mice, like with CF15 cells, we found normalization of amiloride-sensitive Isc. Moreover, oral administration of miglustat (6 days) decreased the amiloride-sensitive Isc in cftr(F508del/F508del) mice but had no effect on cftr(-/-) mice. Our results thus show that rescuing the trafficking-deficient F508del-CFTR by miglustat down-regulates Na(+) absorption. A miglustat-based treatment of CF patients may thus have a beneficial effect both on Cl(-) and Na(+) transports.</b>
PMID: 18309088 [PubMed - as supplie
1: J Pharmacol Exp Ther. 2008 Feb 28 [Epub ahead of print] Links
PARALLEL IMPROVEMENT OF SODIUM AND CHLORIDE TRANSPORT DEFECTS BY MIGLUSTAT IN CYSTIC FIBROSIS EPITHELIAL CELLS.
Noel S, Wilke M, Bot A, De Jonge H, Becq F.
IPBC CNRS UMR 6187.
Cystic Fibrosis, an autosomal recessive disease frequently diagnosed in the Caucasian population, is characterized by deficient Cl(-) transport due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A second major hallmark of the disease is Na(+) hyperabsorption by the airways, mediated by the epithelial Na(+) channel (ENaC). Here we report that in human airway epithelial CF15 cells treated with the CFTR corrector miglustat, whole-cell patch-clamp experiments showed reduced amiloride-sensitive ENaC current in parallel with a rescue of defective CFTR Cl(-) channel activity activated by forskolin and genistein. Similar results were obtained with cells maintained in culture at 27( degrees )C for 24h prior to electrophysiology experiments. With monolayers of polarized CF15 cells, short-circuit current (Isc) measurements also show normalization of Na(+) and Cl(-) currents.<b> In excised nasal epithelium of cftr(F508del/F508del) mice, like with CF15 cells, we found normalization of amiloride-sensitive Isc. Moreover, oral administration of miglustat (6 days) decreased the amiloride-sensitive Isc in cftr(F508del/F508del) mice but had no effect on cftr(-/-) mice. Our results thus show that rescuing the trafficking-deficient F508del-CFTR by miglustat down-regulates Na(+) absorption. A miglustat-based treatment of CF patients may thus have a beneficial effect both on Cl(-) and Na(+) transports.</b>
PMID: 18309088 [PubMed - as supplie