Therapeutics Development for Cystic Fibrosis: A Successful Model for a Multisystem Genetic Disease

Cystic Fibrosis Foundation Therapeutics, Inc., Bethesda, Maryland 20814, USA.
Annual review of medicine (Impact Factor: 15.48). 02/2011; 62:107-25. DOI: 10.1146/annurev-med-061509-131034
Source: PubMed

ABSTRACT Cystic fibrosis (CF) is a progressive genetic disease primarily involving the respiratory and gastrointestinal tracts. Multiple therapies directed at CF symptoms and clinical management strategies have emerged from iterative cycles of therapeutics development, helping to change the face of CF from a fatal childhood affliction to a disease in which nearly 50% of U.S. patients are adults. However, as a consequence of therapeutic advances, the burden of CF care is high, and despite progress, most patients succumb to respiratory failure. Addressing the basic defect in CF with systemic small molecules is evolving as a promising approach. A successful collaboration between a voluntary health organization and a pharmaceutical company, complemented by academic investigators and patients, has led to the clinical development of investigational drugs that restore function to defective CFTR protein in various tissues in CF patients. Important activities, leverage points, and challenges in this exemplary collaboration are reviewed with hope that the CF and other genetic disease communities can benefit from the lessons learned in generating new therapeutic approaches in CF.

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    • "The much ambitioned alternative is to address the basic CF defect(s) systemically with small molecules which can correct, if not all, at least most symptoms notably those involving the airways. Due to intensive high-throughput efforts by companies and a few academic labs, this promising approach has recently evolved as a reality [4]. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in *Address correspondence to this author at the BioFiG -Center for Biodiversity , Functional and Integrative Genomics, Department of Chemistry & Biochemistry, Faculty of Sciences, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal; Tel: +351-21-750 08 61; Fax: +351 21 750 00 88; E-mail: particular, MoA for correctors, i.e., compounds rescuing to the cells surface, the most prevalent mutant in CF patients -F508del-CFTR. "
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    ABSTRACT: Correcting multiple defects of mutant CFTR with small molecule compounds has been the goal of an increasing number of recent Cystic Fibrosis (CF) drug discovery programmes. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in particular of CFTR correctors, i.e., compounds rescuing to the cells surface the most prevalent mutant in CF patients - F508del-CFTR. However, there is increasing evidence that to fully restore the multiple defects associated with F508del-CFTR, different small molecules with distinct corrective properties may be required. Towards this goal, a better insight into MoA of correctors is needed and several constraints should be addressed. The methodological approaches to achieve this include: 1) testing the combined effect of compounds with that of other (non-pharmacological) rescuing strategies (e.g., revertants or low temperature); 2) assessing effects in multiple cellular models (non-epithelial vs epithelial, non-human vs human, immortalized vs primary cultures, polarized vs non polarized, cells vs tissues); 3) assessing compound effects on isolated CFTR domains (e.g., compound binding by surface plasmon resonance , assessing effects on domain folding and aggregation); and finally 4) assessing compounds specificity in rescuing different CFTR mutants and other mutant proteins. These topics are reviewed and discussed here so as to provide a state-of-the art review on how to combine multiple ways of rescuing mutant CFTR to the ultimate benefit of CF patients.
    Current pharmaceutical design 01/2013; DOI:10.2174/13816128113199990318 · 3.29 Impact Factor
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    • "Another pathogenic role of gp78 is in cystic fibrosis (CF). CF is a common autosomal recessive disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), an epithelial anion channel [100]. Deletion of phenylalanine 508 (CFTRF508) is the most common CF-associated mutation, which accounts for about 70% of CF alleles [101]. "
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    ABSTRACT: The endoplasmic reticulum (ER) is the site for maturation of proteins destined for the secretory pathway. Failure in maturation leads to production of misfolded proteins that are eliminated through the ER-associated degradation (ERAD) pathway. ERAD is a complex process that includes misfolded protein recognition, retrotranslocation to the cytosol, ubiquitination and proteasomal degradation. gp78 is an E3 ubiquitin ligase that integrates these ERAD steps by nucleating a unique degradation machine, which uses the p97/VCP-Npl4 complex for retrotranslocation instead of the wellknown p97/VCP-Ufd1-Npl4 complex. A growing list of substrates have been identified for gp78, which highlights the importance of gp78-mediated ERAD in essential physiological pathways and pathological processes.
    Current Protein and Peptide Science 07/2012; 13(5):414-24. DOI:10.2174/138920312802430590 · 2.33 Impact Factor
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    • "Patients currently receive therapeutics primarily aimed at treating symptoms of Cystic Fibrosis (CF; Ashlock and Olson, 2011; Cuthbert, 2011), although the first mechanism-based therapy for CF patients harboring a CFTR gating mutation like G551D was recently approved. For most people with CF this is not a permanent solution, thus new therapies that can target the underlying pathology of the defect are needed. "
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    ABSTRACT: Cystic Fibrosis (CF) is the most common autosomal recessive lethal disorder among Caucasian populations. CF results from mutations and resulting dysfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a cyclic AMP-dependent chloride channel that is localized to the apical membrane in epithelial cells where it plays a key role in salt and water homeostasis. An intricate network of molecular chaperone proteins regulates CFTR's proper maturation and trafficking to the apical membrane. Understanding and manipulation of this network may lead to therapeutics for CF in cases where mutant CFTR has aberrant trafficking.
    Frontiers in Pharmacology 07/2012; 3:137. DOI:10.3389/fphar.2012.00137
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