**Medications to Enhance CFTR Activity**

Terry W. Chin

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130 Cystic Fibrosis in the Light of New Research

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60768

#### **Abstract**

Since the basic defect in cystic fibrosis (CF) involves a defective cell surface protein controlling chloride channel transport across cell membranes, medications which are developed to enhance the cystic fibrosis transmembrane conductance regulator (CFTR) protein should result in improvement in patients with CF. The presence of over 2000 genetic mutations have made these efforts difficult. However, a classifica‐ tion scheme of these mutations has allowed three basic approaches: to bypass missense mutations by having the cellular translation machinery read through the premature stop codon, to enhance the "gating" function of the CFTR protein on the cell surface, and to correct a defective CFTR protein "trafficking" though the cytoplasm to be inserted properly in the cell membrane. This chapter will review clinical trials using drugs which are designed to enhance CFTR protein activity.

**Keywords:** Cystic fibrosis, CFTR, CFTR modulators, CFTR potentiators, CFTR cor‐ rectors, VC-770, ivacaftor, VX-809, lumacaftor, VX-661, PTC124, ataluren

### **1. Introduction**

The identification of the genetic defect in CF allowed the classification of CFTR mutations into six types of mutations. The over 2000 mutations which has been described can be placed in one of these classes: Class I mutations, which may be the result of the genetic mutation resulting in a stop codon or a shift in the reading frame in the messenger RNA which eventually results in a downstream stop codon, do not produce a complete CFTR protein. Class ii mutations result in an altered CFTR protein which is degraded in the endoplasmic reticulum and/or Golgi systems within the cell. Some proteins may be able to make it to the cell surface and have

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variable levels of function (or Class III, IV, or VI effects). Class III mutations result in amino acid substitutions which affect how the CFTR protein is regulated on the cell surface, usually decreasing the channel opening. Class IV mutations result in amino acid substitutions which affect how the CFTR protein functions in its conduction of chloride ions. Class V mutations result in decreased production of normal functioning CFTR protein. Therefore, there is a reduced amount of normal CFTR protein on the cell surface. Finally, class VI mutations are those which affect the stability of CFTR.

Awareness of the types of genetic mutations affecting the normal functioning of the CFTR protein has resulted in searches for treatments directed at various CFTR dysfunctions. This chapter will review recent attempts to develop treatments specific for the various classes of mutations.
