FOUND IT!!
<strong>FINAL ID: </strong>10 <strong>CONTACT NAME: CATEGORY: </strong>CFTR <strong>KEYWORDS: </strong>CFTR, CFTR mutations, G551D, potentiator, preclinical
<strong>Abstract TITLE: </strong>VX-770 POTENTIATION OF CFTR FORMS WITH CHANNEL GATING DEFECTS IN VITRO <strong>AUTHORS (LAST NAME, FIRST NAME): </strong>Van Goor, Fredrick; Yu, Haihui; Burton, Bill; Huang, Tony; Hoffman, Beth; Negulescu, Paul <strong>INSTITUTIONS (ALL): </strong>Vertex Pharmaceuticals Incorporated, San Diego, CA, USA. <strong>ABSTRACT BODY: Abstract Body: </strong>VX-770 is a CFTR potentiator that has been shown to enhance chloride transport and improve lung function, as measured by FEV<span>1, in subjects with CF with the <em>G551D-CFTR </em>mutation. The G551D mutation causes a defect in CFTR channel gating that prevents the channel from opening properly, resulting in a loss of chloride transport. The objective of this in vitro study was to test if VX-770 potentiates CFTR forms produced by other <em>CFTR </em>gating mutations. To do this, CFTR-mediated chloride transport was characterized in electrophysiological studies using recombinant Fisher rat thyroid (FRT) cell lines engineered to express a single mutant CFTR form encoded by a <em>CFTR </em>gating mutation. These included the known CF-causing <em>CFTR </em>gating mutations, G551D, G178R, G551S, G970R, G1244E, S1255P, and G1349D. In addition, single channel patch clamp studies demonstrated that the CF-causing mutations in the <em>CFTR </em>gene, S549N, S549R, and S1251N, are <em>CFTR </em>gating mutations. The baseline level of chloride transport was low (< 10% of normal CFTR function) in FRT cells expressing CF-causing <em>CFTR </em>gating mutations, which is consistent with the low levels of CFTR function as indicated by the high sweat chloride levels (> 80 mmol/L) in patients with CF carrying these mutations. Addition of VX-770 caused a >10-fold increase in CFTR-mediated chloride transport in all the mutations tested, reaching levels equivalent to between 19% and 146% of normal CFTR. For all CF-causing <em>CFTR </em>gating mutations tested, the magnitude of the VX-770 response was similar to or greater than that measured for <em>G551D-CFTR</em>. With the exception of the G1244E mutation, the potency (EC<span>50) of VX-770 was also similar to <em>G551D-CFTR </em>for all <em>CFTR </em>gating mutations tested. These in vitro results showed that VX-770 caused a robust potentiation of mutant CFTR forms encoded by the CF-causing <em>CFTR </em>gating mutations G551D, G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, and S1251N. Supported by Vertex Pharmaceuticals Incorporated..
