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Author Notes:

Address correspondence to: Eric J. Sorscher, 1760 Haygood Drive, Suite 280, Atlanta, Georgia 30322, USA. Phone: 404.727.3293; E-mail: esorscher@emory.edu

Experiments were conducted and designed by CMS, WW, HW, CMM, WJC, and JSH, who also performed data acquisition/analysis.

Reagents were furnished by KLK, JFC, JSH, MM, and EJS.

Data was further analyzed and the manuscript written by CMS, JFC, JSH, KLK, and EJS.

The authors wish to thank J. Tindall for help preparing the manuscript.

E.J. Sorscher is a nonvoting member of the Cystic Fibrosis Foundation Board of Trustees.


Research Funding:

This work was supported by grants from the Cystic Fibrosis Foundation Therapeutics (SORSCH13XX0), the NIH (P30 DK072482), and the National Center for Advancing Translational Sciences of NIH (under UL1TR000454).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine

Analysis of cystic fibrosis-associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases

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Journal Title:



Volume 1, Number 14


Type of Work:

Article | Final Publisher PDF


Emerging knowledge indicates the difficulty in categorizing unusual cystic fibrosis (CF) mutations, with regard to both pathogenic mechanism and theratype. As case in point, we present data concerning P67L mutation of the cystic fibrosis transmembrane conductance regulator (CFTR), a defect carried by a small number of individuals with CF and sometimes attributed to a channel conductance abnormality. Findings from our laboratory and others establish that P67L causes protein misfolding, disrupts maturation, confers gating defects, is thermally stable, and exhibits near normal conductance. These results provide one framework by which rare CF alleles such as P67L can be more comprehensively profiled vis-à-vis molecular pathogenesis. We also demonstrate that emerging CF treatments - ivacaftor and lumacaftor - can mediate pronounced pharmacologic activation of P67L CFTR. Infrequent CF alleles are often improperly characterized, in part, due to the small numbers of patients involved. Moreover, access to new personalized treatments among patients with ultra-orphan genotypes has been limited by difficulty arranging phase III clinical trials, and off-label prescribing has been impaired by high drug cost and difficulty arranging third party reimbursement. Rare CFTR mutations such as P67L are emblematic of the challenges to "precision" medicine, including use of the best available mechanistic knowledge to treat patients with unusual forms of disease.

Copyright information:

© 2016, American Society for Clinical Investigation

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