New Therapeutic Approaches to Modulate and Correct Cystic Fibrosis Transmembrane Conductance Regulator - 27/07/16

Doi : 10.1016/j.pcl.2016.04.006

Thida Ong, MD ^a, Bonnie W. Ramsey, MD ^b,^⁎
^a Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, 4800 Sand Point Way Northeast, M/S OC.7.720, Seattle, WA 98105, USA
^b Department of Pediatrics, Seattle Children’s Research Institute, Center for Clinical and Translational Research, University of Washington, 2001 8th Avenue, Suite 400, M/S CW8-5B, Seattle, WA 98121, USA

^∗Corresponding author.

Résumé

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are clinically available personalized medicines approved for some individuals with cystic fibrosis (CF) to target the underlying defect of disease. This review summarizes strategies used to develop CFTR modulators as therapies that improve function and availability of CFTR protein. Lessons learned from dissemination of ivacaftor across the CF population responsive to this therapy and future approaches to predict and monitor treatment response of CFTR modulators are discussed. The goal remains to expand patient-centered and personalized therapy to all patients with CF, ultimately improving life expectancy and quality of life for this disease.

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Keywords : CFTR modulator, Personalized medicine, Therapeutics, Potentiator, Corrector

Plan

Key points

Introduction

Approaching cystic fibrosis transmembrane conductance regulator: review of structure and function

High-throughput screening to identify cystic fibrosis transmembrane conductance regulator modulators

Augmenting cystic fibrosis transmembrane conductance regulator activity: the potentiator approach

Improved cystic fibrosis transmembrane conductance regulator processing: the corrector approach

Combining potentiator and corrector approaches

Additional modulator therapies

Alternate therapeutic approaches: beyond correctors and potentiators

Approaches to maximize the benefit of cystic fibrosis transmembrane conductance regulator modulators

Lessons from ivacaftor

Summary

T. Ong has nothing to disclose. B.W. Ramsey reports grants from 12th Man Technologies, Catabasis, Corbus Pharmaceuticals, Cornerstone Therapeutics, Flatley Discovery Lab LLV, Gilead Sciences, Inc, GlycoMimetics, Inc, Insmed, Inc, La Jolla Pharmaceutical, Mpex Pharmaceuticals, Inc, Nibalis Therapeutics, Inc, Nordmark, Novartis Pharmaceuticals Corp., Pharmaxis Ltd., Respira Therapeutics, Inc, Sanofi, Savara Pharmaceuticals, Synedgen, Inc, the Cystic Fibrosis Foundation, Vertex Pharmaceuticals, outside the submitted work; and NIH funding: P30DK089507 and ULITR000423.