Two research teams based at the University of Chicago have received prestigious grants from the National Institutes of Health to develop novel medications to treat sleep apnea and asthma.
The grants are designed to accelerate discovery of effective pharmaceutical treatments during the critical second stage of a drug's development, the period between the discovery of a potential new medication and the first round of human clinical trials. The funding--which amounts to about $1.7 million annually for each project for up to five years--is administered by the NIH's Heart, Lung and Blood Institute.
"This support will help speed up the bench-to-bedside process that typically takes decades of research and development," said Julian Solway, MD, the Walter L. Palmer Distinguished Service professor of medicine and pediatrics. "We hope it will bring patients one step closer to medications that could free them from the constant constraints of breathing problems."
The sought-after Centers for Advanced Diagnostics and Experimental Therapeutics in Lung Diseases Stage II grants (known as CADET II grants) were awarded to ten teams nationwide. Each program has already identified and validated a drug target in a significant new treatment approach.
One of the Chicago teams, led by Nanduri Prabhakar, PhD, the Harold Hines Jr. professor of medicine, will focus on developing the first drug to prevent sleep-disordered breathing. The other team, led by Solway, will concentrate on a novel treatment for severe asthma.
New therapies focus on apnea and asthma
Both sleep apnea and severe asthma affect millions of people, but each has limited treatment options.
In sleep apnea, the body fails to regulate breathing when someone sleeps, causing oxygen levels to drop precipitously. Untreated, it can lead to serious health problems, including diabetes, high blood pressure, heart disease, stroke, even brain damage and death.
There are currently no medications to treat sleep apnea. Patients rely on a ventilation-assistance device known as continuous positive airway pressure. This helps patients breathe steadily at night, but it has no effect on the source of the problem.
Prabhakar, who directs the Institute for Integrative Physiology and the Center for Systems Biology of Oxygen Sensing at the University of Chicago, instead hopes to target a chemical signaling system that prompts the body to take each breath. His team has targeted a specific enzyme to regulate breathing.
While there are several effective medications for asthma, approved drugs don't control symptoms for as many as 15 percent of the 20 million Americans with the disease.
"There is an unmet therapeutic need," said Solway, who directs the University of Chicago's Institute for Translational Medicine.
People with severe asthma often remain symptomatic, even when they follow their doctors' guidelines, take high-doses of corticosteroids to reduce inflammation and use long-acting bronchodilators to fight airway constriction.
"We propose a more robust strategy," Solway said.
The team will focus its research on disrupting a molecular process that can cause the smooth muscle that surrounds the airways to contract, making it harder to breathe.
Both projects involve collaboration with groups working at other Chicago institutions. Prabhakar's team is working with Pavel A. Petukhov, PhD, at the University of Illinois at Chicago's newly established Collaborative Engagement in Novel Therapeutic Research and Enterprise (UICentre) to enhance the potential medication. The team will also work closely with the Illinois Institute of Technology's Research Institute, directed by David McCormick, PhD, to characterize the pharmacology and toxicology of the treatment and study how to reduce or manage potential side effects.
Solway's team will work with McCormick and the IITRI on toxicology issues. They will also partner with cell physiologists at Harvard, drug development experts at Purdue, Minnesota and Iowa, as well as medicinal chemists at the NIH's National Center for Advancing Translational Sciences.
Funding for each project comes in two phases. In the first two years, the researchers will work to improve the precise targeting and efficacy of their compounds and examine the absorption, metabolism, distribution and elimination of the drug. If they meet their key milestones, the next three years will focus on understanding all the benefits and potential risks of the drug in animal models and learning how to manufacture the drug and scale up production.
Both teams hope to begin early clinical testing of the resulting medications by 2020.
Sleep undisrupted
In sleep apnea, the systems that regulate breathing malfunction. For people with apnea, oxygen levels in the blood drop precipitously during sleep, sometimes by half. Chronic sleep apnea disrupts sleep, causing constant sleepiness, poor concentration and increased risk of accidents.
Untreated, it can lead to serious health problems, "all sorts of morbidities," Prabhakar said, including "diabetes, high blood pressure, heart disease, stroke, even brain damage and death."
Many patients rely on continuous positive airway pressure, a machine that helps patients breathe steadily at night, but "patients do not like this treatment," Prabhakar said, "and compliance is poor."
For almost 20 years, he and colleagues have focused instead on chemical signals released by the carotid bodies, small clusters of cells that are extraordinarily sensitive to changes in blood oxygen levels. Found in the carotid arteries, on both sides of the throat, these are the primary sensors of blood-oxygen levels. When levels drop, they send signals to brainstem neurons that regulate breathing. This promptly initiates the next breath.
In sleep apnea, however, the carotid bodies can become hypersensitive to certain signals. They no longer react appropriately and thus fail to maintain a steady respiratory rate. As a result, people with severe apneas briefly--or sometimes not so briefly--stop breathing, often hundreds of times a night.
In 2010, Prabhakar and colleagues described a key malfunction that disrupted carotid body responses, triggered by overactivation of an enzyme, cystathionine-gamma-lyase (CSE). This enzyme increases production of hydrogen sulfide. Overstimulation of the system, however, appeared to make the carotid body hypersensitive.
This made Prabhakar's team suspect that CSE was a potential drug target. They developed a small molecule to inhibit its activation. Early tests found that it could normalize sleep-disordered breathing in a rodent model of sleep apnea--also developed by the Prabhakar laboratory.
"Our mice typically have about 60 apneas per hour," Prabhakar said. "Thirty milligrams of our compound produces a marked reduction in apneas. At 90 milligrams they have very few at all."
CADET II funding will enable the team to "optimize our drug for efficacy, potency and safety," Prabhakar said.
"We have a lead compound that can be taken by mouth and a good animal model. The team at UIC will work to make our compound more potent and specific. They have the tools to screen 100,000 related compounds and help us select the most effective.
"We are hoping they can make it ten times more potent," Prabhakar said. "And then David McCormick's unit at IIT can unravel the toxicities and help us improve the chosen compound or how it is administered."
"It's been more than 80 years since the carotid bodies were discovered," Prabhakar said, "work that received the Nobel Prize in 1938. But no one has yet developed a drug that could alter their function. After all that time, there is still a real need for better ways to prevent sleep apnea. I hope this is a light at the end of that tunnel."
Breath unimpaired
For about three million Americans with persistent severe asthma, the approved drugs provide "inadequate symptom control," said Julian Solway. "There is an unmet therapeutic need."
People with severe asthma often remain symptomatic, even when they follow guidelines, taking high-doses of corticosteroids to reduce inflammation, plus long-acting bronchodilators to limit airway constriction.
Both approaches target a "long and complex relaxant-signaling pathway," Solway said. Such complexity can confound signal transmission.
"We propose a more robust strategy," he said. His team has focused on the contractile apparatus, the smooth muscle that surrounds, and in severe asthma, constricts the airways. This muscle has no clearly established beneficial function. That makes it an appealing target.
With support from a previous CADET I grant, Solway's team has already identified a small molecule that interferes with the formation of airway smooth muscle myosin filaments--a key component in muscle performance.
When muscle contracts, myosin filaments tug actin filaments toward the center of the cell. This shortens the muscle's length and, in this setting, narrows the airway it surrounds.
To disrupt this process, the team is now generating derivatives of the lead compound that are even better at preventing myosin proteins from joining together to form filaments, thus preventing airway constriction.
Patients with severe asthma often have unusually muscular airways. Without functioning myosin, however, these muscles cannot contract. These compounds--which the researchers labelled "myosolvins," because they dissolve myosin filaments--dramatically reduce bronchoconstriction in isolated mouse airways.
Dissolving the contractile apparatus is "an entirely novel mechanism of action," Solway said.
"We are bucking a trend here," he added. In this era of personalized medicine, based on complex genetic and physiological variations among individual patients, "our strategy is one of impersonalized medicine," he said. "We target the final effector molecule, a muscle contraction protein that should be identical in almost everyone."
As in the sleep apnea study, the next step is to optimize the potency and safety of the lead compound derivatives and learn the best ways to deliver them by inhalation. If the project meets all of its milestones within the next two years, the IIT toxicology experts will assess the toxicities and look for ways to limit side effects.
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