Cystic fibrosis: Toward personalized therapies

详细信息    查看全文

• 作者：Pauline T. Ikpa ; Marcel J.C. Bijvelds ; Hugo R. de Jonge ; ^{h.dejonge@erasmusmc.nl" class="auth_mail}
• 关键词：CFTR ; cystic fibrosis transmembrane conductance regulator ; rAAV ; recombinant adeno-associated virus ; NBD ; nucleotide binding domain ; MSD ; membrane spanning domain ; iPSC ; induced pluripotent stem cells ; CRC ; conditionally reprogrammed cells ; ROCK ; Rho-kinase ; ICM ; intestinal current measurements ; FIS ; forskolin-induced swelling ; PDE ; phosphodiesterase ; CAL ; Golgi localized CFTR associated ligand ; NHERF ; Na+/H+ Exchanger Regulatory Factor ; Fsk ; forskolin ; NMD ; nonsense-mediated mRNA decay ; PTCs ; p
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：July 2014
• 年：2014
• 卷：52
• 期：Complete
• 页码：192-200
• 全文大小：2164 K

文摘

Cystic fibrosis (CF), the most common, life-threatening monogenetic disease in Caucasians, is caused by mutations in the CFTR gene, encoding a cAMP- and cGMP-regulated epithelial chloride channel. Symptomatic therapies treating end-organ manifestations have increased the life expectancy of CF patients toward a mean of 40 years. The recent development of CFTR-targeted drugs that emerged from high-throughput screening and are capable of correcting the basic defect promises to transform the therapeutic landscape from a trial-and-error prescription to personalized medicine. This stratified approach is tailored to a specific functional class of mutations in CFTR, but can be refined further to an individual level by exploiting recent advances in ex vivo drug testing methods. These tests range from CFTR functional measurements in rectal biopsies donated by a CF patient to the use of patient-derived intestinal or pulmonary organoids. Such organoids may serve as an inexhaustible source of epithelial cells that can be stored in biobanks and allow medium- to high-throughput screening of CFTR activators, correctors and potentiators on the basis of a simple microscopic assay monitoring organoid swelling. Thus the recent breakthrough in stem cell biology allowing the culturing of mini-organs from individual patients is not only relevant for future stem cell therapy, but may also allow the preclinical testing of new drugs or combinations that are optimally suited for an individual patient.

This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.