The complexity of simple genetic disease

Cystic fibrosis is an ion channel disease that interrupts the flow of salts and fluids into and out of cells, and this affects multiple organs. The most serious consequence of the disease is the production of thick mucus in the intestines and lungs, which leads to respiratory complications, the leading cause of death among people with CF.

Cystic fibrosis is an inherited disease.  The causative gene, CFTR, was identified 22 years ago.  Over 1000 mutations associated with CF have been identified since then, many seen in only one patient or a single family.  In the US the most common mutation is F508del; this designation means that the amino acid that is normally the 508th amino acid along the chain that makes the CFTR protein has been deleted. Another mutation, G551D, is found in about 4% of patients in the US -- this mutation replaces one amino acid with another at the 551th position in the protein chain.  

Identifying the CFTR gene created quite a lot of excitement about the potential for gene therapy, but the initial enthusiasm was pretty quickly dampened by the difficulty in transporting a normal copy of the gene to the required sites in the body. A different therapeutic approach was described in a paper in PNAS in 2009.

Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (P_o) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl⁻ secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by ≈10-fold, to ≈50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na⁺ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway. 

The pharmaceutical company that makes VX-770 has just announced the successful completion of a 48 week clinical trial of the drug. The results are impressive. Lung function was significantly improved, and

[h]ighly statistically significant improvements in key secondary endpoints in this study were also reported through week 48. Compared to those treated with placebo, people who received VX-770 were 55 percent less likely to experience a pulmonary exacerbation (periods of worsening in signs and symptoms of the disease requiring treatment with antibiotics) and, on average, gained nearly seven pounds (3.1 kilograms) through 48 weeks. There was a significant reduction in the amount of salt in the sweat (sweat chloride) among people treated with VX-770 in this study. Increased sweat chloride is a diagnostic hallmark of CF. Sweat chloride is a marker of CFTR protein dysfunction, which is the underlying molecular mechanism responsible for CF. People who received VX-770 also reported having fewer respiratory symptoms.     

This is exciting news for the CF community, even for those who don't have the G551D mutation, because the same company is currently testing a drug to correct for the effects of the F508del mutation.

In people with the G551D mutation, CFTR proteins are present on the cell surface but do not function normally. VX-770, known as a potentiator, aims to increase the function of defective CFTR proteins by increasing the gating activity, or ability to transport ions across the cell membrane, of CFTR once it reaches the cell surface. In people with the F508del mutation, CFTR proteins do not reach the cell surface in normal amounts. VX-809, known as a CFTR corrector, aims to increase CFTR function by increasing the amount of CFTR at the cell surface. 

This all has the potential to change the future for people with CF.  And it also means that if the function of a gene and mutations in that gene are understood, the parameters are there for potentially developing therapies.  We seem to understand a lot about this ion channel.  In fact, if these results are real--general, long-lasting, and clinically or lifestyle-important as well as statistically significant -- they probably will apply to many other CF patients with other mutations that are individually rarer but have similar effects on the CFTR protein. 

But, the gene for CF has been known for 2 decades, and a treatment for just  4% of people with the disease is only now beginning to look promising.  The difficulty of getting to just this point is a sobering reminder that 'personalized medicine' is going to be an order of magnitude harder for polygenic diseases.  And hopefully, we won't have to take back these positive feelings about these potentially life changing results, and this 48 week trial is not being reported prematurely to boost stock prices or anything cynical like that.

If it works as the current story suggests, these results exemplify what we personally have repeatedly said about medical genetics.  There really are good ways to spend genetics research effort, not on mindless GWAS mapping, but on traits that are tractably simple and that really are genetic in a meaningful sense.  This seems like a very good example of that principle even if, as is the case with other instances, only a fraction of all CF patients will benefit directly.