ous impact on protein coding. Interestingly, all of the SNPs identified in Caucasian patients lie in tight linkage disequilibrium to one another, and an antisense nested gene is located in this region of the chromosome as well, though the function of the nested gene is not yet known.

An important limitation of the research done to date is that the marker has been identified in one population—non-Hispanic Caucasians—but the genetics of the region are different in African Americans. Researchers now need access to samples from other populations to determine whether the marker is useful for identifying patients from other races and ethnicities.

Because of the limited biological understanding, there was no a priori hypothesis for genetic-based drug discovery and development in this case, Nisenbaum concluded. Rather, hypotheses needed to be generated in Phase II, and these hypotheses then needed to be replicated and validated in Phase III. Also, as was the case with crizotinib, if Phase III results support the need for a companion diagnostic, the development of that diagnostic will need to be timed appropriately so that it does not become the rate-limiting factor for the drug approval.


Cystic fibrosis is an orphan disease, which differentiates it from cancer and schizophrenia, said Peter Mueller of Vertex Pharmaceuticals. The disease is linked to a genetic defect that leads to an impairment in the ability of cystic fibrosis transmembrane conductance regulator (CFTR) channels to pump chloride and other ions across cell membranes due to either incorrect localization of the protein in the cell or production of nonfunctional proteins. This lack of ion transport causes a variety of adverse outcomes, including the accumulation of a sticky mucus which is characteristic of cystic fibrosis and which eventually leads to chronic infections and death.

More than 1,700 mutations have been linked to impairment of the CFTR channel, which makes gene therapy difficult, Mueller said. Instead, his company has sought to develop small molecules that are orally bioavailable and that improve CFTR function, thereby reducing and halting the progression of the disease.

The mutations responsible for cystic fibrosis can be divided into three categories. People with CFTR gating mutations express channels on the surface of their cells that do not function properly. People with residual CFTR function express a minimal number of channels on their cell surface that do not work optimally. And the largest group consists of people who have almost no CFTR function due to a failure to express channels on cell surfaces.

Understanding the underlying genetics and biology behind the loss of

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