This video excerpt from NOVA examines the promise and realities of developing drugs designed to treat genetic disorders. The video presents the story of one patient, Michael McCarrick, whose lungs were devastated from years of suffering from cystic fibrosis. After researchers identified the gene involved in cystic fibrosis, it took decades to find ways to fortify the faulty protein responsible for the serious illness. While two drugs, including one called Kalydeco, offer a small number of patients hope that they will not have to endure a lung transplant, it may be years and several hundred million more development dollars before effective drugs are available for a wider population.
As scientists continue to study the human genome, they can better understand how the different groupings of bases that make up our genes control their function. A better understanding of proper gene function offers scientists important insights into gene malfunction, which can lead to serious diseases. Scientists have successfully identified the genes responsible for hundreds of inherited diseases. But finding the genetic causes of diseases has yet to yield a bounty of ways to treat them.
Even before the Human Genome Project produced a “rough draft” of the human genetic code in 2003, scientists were already touting gene therapy as a cure for genetic diseases. Doctors might simply insert normal genes in place of malfunctioning ones. The normal genes would take over, produce the right kinds of proteins, and any problem would be solved. But this elegant solution has yet to be realized. For one inherited disease, cystic fibrosis (CF), the biology proved much more complicated than scientists anticipated. Cystic fibrosis causes sticky mucus to block tubes and ducts in the lungs, pancreas, intestines, and other areas the body. Because a buildup of mucus makes it easy for bacteria to grow, serious lung infections develop that, repeated over time, can severely damage the lungs. For CF patients, breathing becomes more and more difficult with time.
Cystic fibrosis was considered by many to be a prime disease candidate for gene therapy. Unlike diseases that involve multiple genes, people with CF inherit just one faulty recessive gene from each parent. However, every clinical trial failed. The modified viruses used to deliver the normal genes had trouble getting past the mucus to the cells that needed them. Even those that made it were unable to hijack the cells and replicate, as viruses normally do. So some researchers tried a different approach: they developed drug compounds to correct the function of the faulty protein made by the CF gene (CFTR). The challenge of designing a drug is daunting and involves a tremendous amount of trial and error; 600,000 compounds were tested to develop Kalydeco. Drug development timelines of 20 years or more at a cost of hundreds of millions of dollars are common in pharmaceuticals.
Decades before Michael McCarrick appeared in this video, researchers identified the most common genetic defect behind the disease—three missing letters in the CFTR gene. However, there are more than a thousand other mutations that can also produce CF, and different mutations cause different defects in the CFTR protein, resulting in milder or more severe forms of the disease. The experimental drug that McCarrick took, Kalydeco, and other so-called CFTR modulators are therapies designed to correct the function of the defective protein. While the drug was not able to save McCarrick—the damage to his lungs proved too great, and he died two months after the video was made—both adult and pediatric treatment groups in a clinical trial showed improved lung function and an increase in weight and other quality of life measures, with few safety issues. Kalydeco was approved by the FDA in January 2012, becoming just the fourth drug approved to counteract the effects of a specific gene mutation to make it to market.
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