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Cystic Fibrosis Channel (CFTR) in the cell membrane; ivacaftor works on the outside of the cell to increase the ease with which chloride ions can move through the channel formed by CFTR protein that spans the cell membrane many times

It seemed like a major medical miracle at the time: the defective gene which causes cystic fibrosis (CFTR gene which stands for Cystic Fibrosis Transmembrane Conductance Regulator) was identified and the world was waiting for the next step, perhaps a quick cure for the disease which many hoped would be realized shortly after discovery of the offending gene. After all, knowledge of the gene and the amino acid sequence of CFTR seemed like overcoming the major hurdle and the rest would be easy–a drug designer game–no problem. The CFTR gene identification however, was in 1989 and, although improvements in palliative therapeutic methods over the past forty years have dramatically prolonged the survival rate of those  afflicted with the disease (from an average age of 11 years to 37), no magical cure had emerged more than twenty years since the gene was first discovered. Now, very recently, the drug VX-770 (ivacaftor) was introduced that seems to offer a breakthrough for at least one subclass of patients with Cystic Fibrosis. As it turns out, Cystic Fibrosis is a disease that contains many different mutations of the CFTR gene, and only the mutation known as G551D, which has defective CFTR proteins that reach the surface of the cell are responsive to the drug (ivacaftor works by enhancing the transport of chloride through the CFTR channels, which improves the ability of the channel to participate in normal fluid regulation, reducing the sticky mucous secretions that, in the respiratory system, create a high risk of infection and restriction to normal air flow and oxygen exchange).  The G551D  mutation only accounts for 4 to 5% of the Cystic Fibrosis population. But the hope is that this drug will also help other mutations of the gene if they have at least some CFTR channels that make it to the surface of the cell.

Most of the cystic fibrosis patients have defects in the protein such that they never get placed in the cell membrane, because they are not folded properly and not recognized by the cell “as suitable for service.” Once the CFTR protein is properly placed in the cell membrane, it works by allowing chloride ions to more readily traverse the ion channel that they form, typically moving from the inside to the outside of the cell (with sodium and water coming through other channels) to provide a less viscous secretion into the respiratory tracts (other organs besides the lungs are similarly affected). Thus, while no single drug is likely to  relieve the entire panoply of cystic fibrosis mutations, this first step using ivacaftor has proven very promising in clinical trials. It is a novel drug that was created by twenty years of intensive research and new discoveries along the way that verified how complex a problem we face in generating a suitable cure, even if the structure of the disease-causing protein has been deciphered. VX-770 (ivacaftor) was developed by a method known as High Throuput Screening (HTS) in which 228,000 chemically diverse drug-like compounds were screened using a cellular assay for identifying CFTR potentiators. A multiple author paper was published in PNAS in 2009 and the results of a successful clinical trial were reported in the November 3, 2011 issue of the New England Journal of Medicine.

While this promising new drug gives us all reason to celebrate and enhance our hopes for future developments in this dreaded disease, we must also sober up for the struggle ahead, because this new drug (ivacaftor) does not address the central problem faced by the majority of patients with cystic fibrosis. About 90% of cystic fibrosis patients suffer from a form of the disease in which they do not produce a CFTR protein that partitions across  the cell membrane and would thus not be amenable to ivacaftor treatment. In a way, the drug works like hooking up your hose to a power washer, which increases the pressure and flow of water, but would not work without a source of water and the plumbing necessary to bring it to the device. The task ahead for the majority of cystic fibrosis patients is more sobering when compared to the achievement with ivacaftor and the subset of patients with G551D. Indeed a more complete cure, covering the entire spectrum of the cystic fibrosis patient population will very likely have to come from a gene replacement  strategy. But we have good news on that front as well: we have already had success with therapeutic gene-replacement approach in treating diseases such as Leber’s Congenital Amaurosis, through the injection of a single dose of adenovirus into the eye which had a copy of a healthy gene that replaced the defective RPE65 gene. RPE65 is required to regenerate the visual pigment (rhodopsin) that is necessary for the first step in capturing photic stimuli. Thus the patients with this deficiency were blind from an early age. Now the treated subjects can see and this mode of therapy will spread to eventually include many different forms of blindness, including retinitis pigmentosa, one of the major causes of human blindness.

It was once the case that drug therapy development was by fortuitous accident. The delay between the discovery of the gene and the first drug to target and improve CFTR action points out the difficulty that modern medicine faces: the transition from the era of chemical medicine (where you use the shotgun approach to try a lot of things and if one works you often don’t know why–such as the accidental discovery that antihistamines (chlorpromazine) dramatically improved some symptoms of schizophrenia and led to the elimination of several hundred thousand hospital beds in the 1950s that had been devoted to their care–even though the drug does not cure the disease) to molecular medicine (where the drug is designed to interact with targeted features of the offending molecule, or you replace the gene or prevent its expression)–can be a long, arduous and very painful process, filled with moments of hope and despair much like the medical quest for an AIDS vaccine; it is now more than thirty years since the AIDS virus was first discovered. We keep thinking that we will shorten the delay between discovery and cure, that each new breakthrough towards adopting molecular approaches will allow us to reach a threshold where a new pathway is illuminated to light the way for quickly curing all genetically-based diseases through a magical form of gene replacement therapy, while non-inherited chronic diseases will be cured with greater precision in drug development, like the results with ivacaftor. Each breakthrough like ivacaftor  treatment for cystic fibrosis gives us hope that we are approaching such a threshold and that we are getting closer to a  much broader and wiser view of the disease landscape.  But to get there, we still have to get a lot smarter about biology before any kind of medical avalanche for cures will flood the broad human pathology terrain.

When I was a medical student, during my rotation in medicine as a clinical clerk in my junior year, we admitted a young girl to the hospital with a raging pneumonia caused by her cystic fibrosis condition. It was a life-threatening situation, but she was finally discharged after a long period of antibiotic and pulmonary therapy. She was about 12 and was full of energy with high expectations for her future, though by then she had been admitted many times to the hospital with similar infections and she had obviously been afflicted with the disease from the time of her birth. The disease had also retarded her growth. It seemed like everyone in the hospital went out of their way to greet this young patient, as she was cheerful, charming and expressed with optimism the idea that she might have passed the most dangerous period of her disease and could now look forward to a future with more certainty and plan accordingly. Yet, a year later, I learned that she had been admitted again with another bout of pneumonia and died in the hospital. I never forgot that young patient and I think that experience accounts for my long-standing interest in cystic fibrosis and the CFTR ion channel.

RFM