Breathing Easier
Cystic fibrosis patients could soon benefit from breakthrough small-molecule drugs that treat their underlying disease instead of just their symptoms
http://pubs.acs.org/cen/coverstory/86/8635cover.html
Lisa M. Jarvis
ON A TYPICAL school morning, Jeanmarie Youngblood wakes up at 4:45 AM to start her daily routine, an hour and 20-minute ordeal that doesn't even include a bowl of cereal. If this was a case of typical teenage-girl vanity, she might be spending the time showering, blow-drying her straw-colored hair, and picking out the right pair of skinny jeans. But for Youngblood, setting her alarm for that bleary-eyed hour isn't about looking good in homeroom. It's about getting her lungs in shape for the day.
Vertex PharmaceuticalsBREAKTHROUGH Scientists at Vertex Pharmaceuticals have discovered drugs to treat the genetic defect that causes cystic fibrosis.
Youngblood has cystic fibrosis, a disease that causes thick, sticky mucus to clog her lungs and disrupt her digestive tract. It's a trait she shares with some 30,000 other Americans who inherited a copy of an errant gene from both their mother and father.
The first order of business when Youngblood stumbles down the stairs of her Brooklyn, N.Y., home is to attach a hose to her nebulizer, a device that aerosolizes a drug, and then load it with albuterol, which opens the airways in her lungs. Next, she puts on a specially designed vest that compresses and releases her chest wall. Looking like a life jacket, it gives a vigorous massage that helps loosen the mucus in her chest and keeps an otherwise persistent cough at bay. For the 30 minutes she wears the vest, she inhales hypertonic saline, a recent addition to the routine that helps to thin and clear mucus.
After that, Youngblood changes the hose on her nebulizer yet again to inhale Tobi, an aerosolized version of the antibiotic tobramycin. Another hose change, and she breathes in Pulmozyme, an enzyme that snips the extracellular DNA in the lungs' mucus, an additional method of thinning everything out.
She repeats the entire routine, without the Pulmozyme, around dinnertime. Keeping up with the nearly three-hour-per-day program is no small feat. "It's a lot of time I spend sitting, not being able to do things," Youngblood concedes. Yet it is also a fact of her teenage life, something that she has to do to feel okay.
Cystic fibrosis boils down to a hydration problem. The mucus lining our lungs, just like the stuff that lines our nostrils, acts like flypaper, catching bacteria, dust, viruses, and other particles we inhale. The cilia then sweep that mucus out, a process we see in action when we have a cold.
But the level of hydration needs to be just right to keep the mucus flowing. There is a delicate balancing act going on inside our lungs: Salt is being absorbed and secreted to draw water in and out, maintaining a consistent thin layer of fluid on our airways.
That balance is off in people with cystic fibrosis. They all have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which carries the instructions for making a protein that shuttles chloride ions from one side of a cell membrane to the other. CF patients absorb too much salt and have trouble secreting it; as a consequence, their lungs are dotted with dried-out pockets that get clogged with thick mucus. The pockets are a breeding ground for bacteria. Patients are afflicted with chronic infections, most commonly caused by a nasty bug called Pseudomonas aeruginosa.
"The ultimate irony is that in your lungs right now you have about 10 mL, or one-third of a teaspoon, of water on your airways," says Richard Boucher, director of the Cystic Fibrosis Pulmonary Treatment & Research Center at the University of North Carolina (UNC), Chapel Hill. "In CF, at least early in life, you have almost none." All that doctors are trying to do throughout the course of a CF patient's life is replenish that tiny bit of fluid and keep it there.
IT'S A TASK that is much easier said than done with existing treatments. To date, patients have been stuck with drugs that treat their symptoms rather than the underlying disease causing them. Youngblood's regime, for example, is mostly palliative: The goal is to keep her Pseudomonas infection from getting out of control while breaking up enough mucus in her lungs so she can breathe easier and cough less often.
CF FoundationBREATHE IN CF patient Zach Berkley uses a nebulizer as part of his therapy.
But in the next few years, a stream of new small-molecule drugs aimed squarely at repairing the hydration balance could reach patients. The drugs offer the potential to not only improve the health of CF patients like Youngblood but also dramatically change the outlook for people newly diagnosed with the disease. And because some of the drugs are in pill rather than aerosol form, they could make life a lot easier for patients.
This promising pipeline would not exist without the ambitious efforts of the Cystic Fibrosis Foundation, which has funded much of the discovery and development of those products through its investment arm, Cystic Fibrosis Foundation Therapeutics. The nonprofit organization provides incentives to companies to develop products for a relatively small group of patients who seek newer and better drugs (C&EN, May 7, 2007, page 19).
The need for better drugs is acute. It is virtually impossible to get rid of bacteria once they take up residence in a patient's lungs, says Bob Beall, president of the CF Foundation. Their presence sets off a vicious, lifelong cycle of treatment for patients. "They use antibiotics, the infection comes back; they use them again, it comes back again," Beall says. "Eventually, every infection takes its toll on lung function. Eventually, most patients die of lung destruction."
That harsh reality is why patients like Youngblood work so hard to keep those infections under control. Even with her daily routine, Youngblood spends a few days in the hospital each year as a housekeeping exercise to clear out a persistent Staphylococcus infection. Before Tobi was introduced in 1998, Youngblood had to make additional hospital visits to treat her Pseudomonas infection.
Furthermore, CF is not only a problem of the lungs. That sticky mucus blocks the movement of enzymes in the pancreas, making it difficult for CF patients to absorb nutrients; eventually, pancreatic function breaks down entirely. So in addition to her twice-daily lung-treatment routine, Youngblood swallows five pills containing enzymes at every meal or snack to help her intestines absorb much-needed nutrients. She also takes multivitamins, salt pills, and the inhaled asthma treatment Singulair daily and the antibiotic Zithromax three times per week.
Such routines have been effective. When the CF Foundation was established in 1955, patients barely lived to school age. By the 1980s, with more antibiotics available, life span was extended to the late teens. Today, because of more effective drugs, patients generally live to be older than age 37.
The drugs offer the potential to not only improve the health of CF patients but also dramatically change the outlook for people newly diagnosed with the disease.
But the foundation thinks it can do much better. "We've always felt that if we could find out why those thick, tenacious secretions are building up, we could stop that buildup, thin out the secretions, and maybe bacteria won't even want to live there," Beall says. "If we could treat the basic defect, we could have a better potential for treating the disease."
The CFTR gene was discovered in 1989, but it took years of research to unravel how it was actually causing the disease. "It wasn't really until we developed the systems that allowed us to understand that these CF patients were missing this thin film of liquid that it really became obvious how the whole pathogenesis of CF evolved," UNC's Boucher says.
Armed with that information, drug companies are taking two approaches to addressing the underlying disease. One camp is trying to correct the genetic defect—that is, to actually manipulate the formation of the CFTR protein to render it functional. The other camp is working on opening alternative routes for transporting salt to the lining of the lungs and intestines. Beall says both show promise and even have the potential to be used together for maximum effect.
Vertex Pharmaceuticals has been working with the CF Foundation on figuring out how to fix the broken chloride channel for nearly a decade. In the late 1990s, the nonprofit enlisted Aurora Biosciences, which was later acquired by Vertex, to develop functional assays that could be used to find molecules that corrected CFTR function.
Cystic fibrosis patients could soon benefit from breakthrough small-molecule drugs that treat their underlying disease instead of just their symptoms
http://pubs.acs.org/cen/coverstory/86/8635cover.html
Lisa M. Jarvis
ON A TYPICAL school morning, Jeanmarie Youngblood wakes up at 4:45 AM to start her daily routine, an hour and 20-minute ordeal that doesn't even include a bowl of cereal. If this was a case of typical teenage-girl vanity, she might be spending the time showering, blow-drying her straw-colored hair, and picking out the right pair of skinny jeans. But for Youngblood, setting her alarm for that bleary-eyed hour isn't about looking good in homeroom. It's about getting her lungs in shape for the day.
Youngblood has cystic fibrosis, a disease that causes thick, sticky mucus to clog her lungs and disrupt her digestive tract. It's a trait she shares with some 30,000 other Americans who inherited a copy of an errant gene from both their mother and father.
The first order of business when Youngblood stumbles down the stairs of her Brooklyn, N.Y., home is to attach a hose to her nebulizer, a device that aerosolizes a drug, and then load it with albuterol, which opens the airways in her lungs. Next, she puts on a specially designed vest that compresses and releases her chest wall. Looking like a life jacket, it gives a vigorous massage that helps loosen the mucus in her chest and keeps an otherwise persistent cough at bay. For the 30 minutes she wears the vest, she inhales hypertonic saline, a recent addition to the routine that helps to thin and clear mucus.
After that, Youngblood changes the hose on her nebulizer yet again to inhale Tobi, an aerosolized version of the antibiotic tobramycin. Another hose change, and she breathes in Pulmozyme, an enzyme that snips the extracellular DNA in the lungs' mucus, an additional method of thinning everything out.
She repeats the entire routine, without the Pulmozyme, around dinnertime. Keeping up with the nearly three-hour-per-day program is no small feat. "It's a lot of time I spend sitting, not being able to do things," Youngblood concedes. Yet it is also a fact of her teenage life, something that she has to do to feel okay.
Cystic fibrosis boils down to a hydration problem. The mucus lining our lungs, just like the stuff that lines our nostrils, acts like flypaper, catching bacteria, dust, viruses, and other particles we inhale. The cilia then sweep that mucus out, a process we see in action when we have a cold.
But the level of hydration needs to be just right to keep the mucus flowing. There is a delicate balancing act going on inside our lungs: Salt is being absorbed and secreted to draw water in and out, maintaining a consistent thin layer of fluid on our airways.
That balance is off in people with cystic fibrosis. They all have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which carries the instructions for making a protein that shuttles chloride ions from one side of a cell membrane to the other. CF patients absorb too much salt and have trouble secreting it; as a consequence, their lungs are dotted with dried-out pockets that get clogged with thick mucus. The pockets are a breeding ground for bacteria. Patients are afflicted with chronic infections, most commonly caused by a nasty bug called Pseudomonas aeruginosa.
"The ultimate irony is that in your lungs right now you have about 10 mL, or one-third of a teaspoon, of water on your airways," says Richard Boucher, director of the Cystic Fibrosis Pulmonary Treatment & Research Center at the University of North Carolina (UNC), Chapel Hill. "In CF, at least early in life, you have almost none." All that doctors are trying to do throughout the course of a CF patient's life is replenish that tiny bit of fluid and keep it there.
IT'S A TASK that is much easier said than done with existing treatments. To date, patients have been stuck with drugs that treat their symptoms rather than the underlying disease causing them. Youngblood's regime, for example, is mostly palliative: The goal is to keep her Pseudomonas infection from getting out of control while breaking up enough mucus in her lungs so she can breathe easier and cough less often.
But in the next few years, a stream of new small-molecule drugs aimed squarely at repairing the hydration balance could reach patients. The drugs offer the potential to not only improve the health of CF patients like Youngblood but also dramatically change the outlook for people newly diagnosed with the disease. And because some of the drugs are in pill rather than aerosol form, they could make life a lot easier for patients.
This promising pipeline would not exist without the ambitious efforts of the Cystic Fibrosis Foundation, which has funded much of the discovery and development of those products through its investment arm, Cystic Fibrosis Foundation Therapeutics. The nonprofit organization provides incentives to companies to develop products for a relatively small group of patients who seek newer and better drugs (C&EN, May 7, 2007, page 19).
The need for better drugs is acute. It is virtually impossible to get rid of bacteria once they take up residence in a patient's lungs, says Bob Beall, president of the CF Foundation. Their presence sets off a vicious, lifelong cycle of treatment for patients. "They use antibiotics, the infection comes back; they use them again, it comes back again," Beall says. "Eventually, every infection takes its toll on lung function. Eventually, most patients die of lung destruction."
That harsh reality is why patients like Youngblood work so hard to keep those infections under control. Even with her daily routine, Youngblood spends a few days in the hospital each year as a housekeeping exercise to clear out a persistent Staphylococcus infection. Before Tobi was introduced in 1998, Youngblood had to make additional hospital visits to treat her Pseudomonas infection.
Furthermore, CF is not only a problem of the lungs. That sticky mucus blocks the movement of enzymes in the pancreas, making it difficult for CF patients to absorb nutrients; eventually, pancreatic function breaks down entirely. So in addition to her twice-daily lung-treatment routine, Youngblood swallows five pills containing enzymes at every meal or snack to help her intestines absorb much-needed nutrients. She also takes multivitamins, salt pills, and the inhaled asthma treatment Singulair daily and the antibiotic Zithromax three times per week.
Such routines have been effective. When the CF Foundation was established in 1955, patients barely lived to school age. By the 1980s, with more antibiotics available, life span was extended to the late teens. Today, because of more effective drugs, patients generally live to be older than age 37.
The drugs offer the potential to not only improve the health of CF patients but also dramatically change the outlook for people newly diagnosed with the disease.
But the foundation thinks it can do much better. "We've always felt that if we could find out why those thick, tenacious secretions are building up, we could stop that buildup, thin out the secretions, and maybe bacteria won't even want to live there," Beall says. "If we could treat the basic defect, we could have a better potential for treating the disease."
The CFTR gene was discovered in 1989, but it took years of research to unravel how it was actually causing the disease. "It wasn't really until we developed the systems that allowed us to understand that these CF patients were missing this thin film of liquid that it really became obvious how the whole pathogenesis of CF evolved," UNC's Boucher says.
Armed with that information, drug companies are taking two approaches to addressing the underlying disease. One camp is trying to correct the genetic defect—that is, to actually manipulate the formation of the CFTR protein to render it functional. The other camp is working on opening alternative routes for transporting salt to the lining of the lungs and intestines. Beall says both show promise and even have the potential to be used together for maximum effect.
Vertex Pharmaceuticals has been working with the CF Foundation on figuring out how to fix the broken chloride channel for nearly a decade. In the late 1990s, the nonprofit enlisted Aurora Biosciences, which was later acquired by Vertex, to develop functional assays that could be used to find molecules that corrected CFTR function.
