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Finding new drugs to enhance anion secretion in cystic fibrosis: Toward suitable systems for better drug screening. Report on the pre-conference meeting to the 12th ECFS Basic Science Conference, Albufeira, 25–28 March 2015

Alan S. Verkman, Aleksander Edelman, Margarida Amaral, Marcus A. Mall, Jeffrey M. Beekman, Torsten Meiners, Luis J.V. Galietta, and Christine E. Bear

Introduction

Cystic fibrosis (CF) has a complex and chronic manifestation, with the severity and types of symptoms differing widely from person to person depending on their specific genetic mutation, their environment and their genetic background. Individuals with CF have treatment plans aimed at ameliorating the debilitating symptoms of their disease, including difficulties in breathing, recurrent lung infections and digestive disorders. The year 2012 marked a turning point for certain eligible CF patients — KALYDECO™ was approved as a therapy for a small group of CF patients exhibiting the G551Dmutation [1] and eight other rare CFTR mutations in the CFTR gene. KALYDECO ™, whose active principle is the potentiator Ivacaftor, acts to directly repair the defect in CFTR channel activity, instead of a symptom-based approach traditionally used to treat CF patients. The positive clinical effects of this medication have been remarkable and life-changing for this small CF patient group. The major CF-causing mutation, F508del, present on at least one allele in 85% of CF subject cases [2], causes multiple defects in protein folding, assembly, and functional expression and hence, improvement by pharmacological modulators presents a significant challenge.

The CF community was excited to learn that lung function was observed in a Phase III clinical trial [3] of Ivacaftor plus the compound Lumacaftor, a “corrector” compound that acts to partially improve F508del-CFTR biosynthesis, processing and stability [4]. This co-therapy (Orkambi™) was recently approved by the FDA as a treatment for CF patients who are homozygous for the major mutation. However, heterogeneity in the clinical response to Orkambi™ by this patient cohort, highlights the importance of developing novel compounds in order to effectively treat everyone with this mutation. The research community recognizes the need to identify more effective compounds targeting the defects caused by F508del-CFTR (and other mutations not currently targeted in drug discovery programs), to develop in-vitro tools to stratify responsive patients, and to identify compounds for rational alternative targets in order to provide companion therapies [5].

Following from an initial seminar in 2014 [6] which addressed CFTR functional measurements in human models for diagnosis, prognosis and personalized therapy, this preconference seminar to the ECFS Basic Science Conference was held in Albufeira (Portugal) on March 25–28, 2015. Novel drug screens conducted using unique, mechanism-based discovery platforms were discussed. Strategies for identifying small molecules that target epithelial channels (other than CFTR) known to modulate epithelial fluid transport and potentially compensate for the lack of CFTR function were described. Such strategies may be advantageous in therapy development for patients bearing mutations that are not directly amenable to pharmacological correction. Further, the need to complement ion channel activity studies with measurements of more complex epithelial functions, i.e., ciliary beating and mucus rheology in order to optimize the capacity of in-vitro assays to predict clinical efficacy was discussed. Finally, a EU screening facility that will enhance progress in drug discovery was described. This facility will engage with scientists to implement the next generation of drug discovery platforms and provide effective mutation and patient-targeted therapies.

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