Aeolus Pipeline Initiative: Cystic Fibrosis

According to the Cystic Fibrosis Foundation, about 30,000 Americans, 20,000 Europeans, and 3,000 Canadians have Cystic fibrosis (CF). In the United States, about 12 million people are carriers.

Cystic fibrosis is the most common fatal, inherited disease in the United States. CF alters the mucus secretions of the body’s epithelial cells. Epithelial cells make up the outside layer of tissue that lines every open surface of the body, inside and out, including the various tunnels and cavities in the lungs, urinary tract, liver, and reproductive tract. In patients with CF, the mucus that the epithelial cells secrete is much thicker and stickier than normal. It blocks the flow of pancreatic juices in the pancreas, impeding digestion and the absorption of fats and fat-soluble vitamins, leading to nutrition deficiencies and intestinal complications. It clogs the airways of the lungs, blocking the flow of air and making the tissue vulnerable to continual lung infections.

CF is a genetic disease resulting from the inheritance of a defective recessive gene. A recessive gene is one that is expressed only when both copies of the gene are present, so a person with CF must have inherited the gene that causes CF from both parents. A person who has only one copy of the gene is known as a "CF carrier." The defective gene that causes CF codes for a protein responsible for salt (sodium chloride) transport by the epithelial cells. There are several hundred possible mutations that can lead to CF symptoms. The severity of symptoms varies depending on the particular mutation.

The disease affects all racial and ethnic groups, although it affects Caucasians with northern European ancestry more often than other populations. It is the most common recessive genetic disorder in Caucasians, occurring in about 1 out of every 1,600 births. In African Americans, CF affects 1 in 13,000 babies; in Asian Americans, 1 in 50,000 is affected. One in 22 Caucasians are carriers. Genetic testing can identify carriers, but the tests are only 80%-85% accurate because not all of the several hundred mutations that can cause CF are detectable.

Before the mid-1960s, the median age of death of children with CF was 2 years. That means that one-half of babies born with CF died by the age of two. By the early 1990s, the median age of death had increased to 25 years. It is predicted that babies born with CF in the 1990s can expect to live for 40 years or more. Today, nearly 40 percent of the CF population is age 18 and older. Adults, however, may experience additional health challenges including CF-related diabetes and osteoporosis. CF also can cause reproductive problems—more than 95 percent of men with CF are sterile. Although many women with CF are able to conceive, limited lung function and other health factors may make it difficult to carry a child to term.

Infectious processes drive the progressive lung disease associated with CF. This condition is thought to cause an imbalance in the lung’s antioxidant defense system leading to severe oxidative stress. However, recent studies suggest that the CF gene defect itself may be an important component of the imbalance in the lung’s antioxidant defenses by modulating glutathione transport into the epithelial lining fluid (Am J Physiol., 275: C323-326.1, 1998). This, together with malabsorption of essential dietary antioxidants, may make the cystic fibrosis patient less capable to defend against the infectious processes that ultimately destroy the lung (Am J Clin Nutr., 61:843-847, 1995; J Pediatr., 122:703-707, 1983.) This forms the rationale for a therapeutic approach to use catalytic antioxidants, such as AEOL 10150 and compounds from the Pipeline Initiative, in CF to correct this antioxidant imbalance and slow the progression of tissue destruction in the lung.

There is ample evidence in the literature describing oxidative stress in the CF patient (Am J Clin Nutr 61: 843-847 (1995); Free Radic Biol Med 18: 801-806, 1995); Thorax 52:557-560 (1997); Pediatr Res 33:247-250, (1997).

It is well recognized that infections can lead to the overproduction of reactive oxygen and nitrogen species (ROS/RNS) that can damage tissue (see figure below). ROS/RNS are integral parts of the host defense and are released by activated white blood cells in response to bacterial and viral infections. Tissue injury itself can increase oxidant formation by injury of mitochondria, release of redox active iron and increased activity of calcium sensitive oxidases such as xanthine oxidase. Overproduction of ROS/RNS can deplete tissue antioxidants and set up an imbalance that can further contribute to tissue injury and impairment of repair mechanisms (Am J Med 91: 39S-44S, 1997).

ROS/RNS that are formed during infection and may be involved in tissue injury (modified from (Adv Pharmacol 38: 491-513, 1997). .

If an imbalance in the antioxidant defenses were inherent with the gene defect itself, as suggested (Am J Physiol 275:C323-326.1, 1997) then the CF patient would be less able to defend against oxidative stress. Data from CFTR mutant mice supports the concept in those mice that lack functional CFTR have exaggerated inflammatory responses to pseudomonas infections and increased mortality (J Clin Invest 100:2810-2815,1997).

Also, it has been reported that CF patients have much lower concentrations of glutathione in their lung surface lining fluid than normal individual (J Appl Physiol 75:2419-2424,1993). However, it is not clear whether this deficit in lung glutathione is due to chronic oxidative stress or the CFTR gene defect or both.

It is becoming clear that the use of antioxidants may be beneficial in CF patients, regardless on whether the gene defect or the infectious processes or a combination of both processes produces the antioxidant imbalance in the lungs of CF patients.

The use of new animal models to model CF disease are useful to investigate the imbalance between oxidative stress and antioxidants. We have started a collaboration with a group of researchers at the University of North Carolina using a recently developed genetic mouse model (Scnn1b) that presents with a lung disease that highly resembles that seen in CF patients (Nature Medicine 10(5): 487-493, 2004).

Studies are underway looking at the efficacy of AEOL 10150 in preventing the massive inflammation and lung destruction in these mice. Preliminary results suggest that subcutaneous administration of AEOL 10150 does provide an enhancement in the life-cycle of these animals.

With subcutaneous dosing beginning 3 days after birth, and survival measured at day 10, Scnn1b animals (n = 10) treated with AEOL 10150 evidenced a 50% survival rate, while saline treated Scnn1b controls (n = 6) evidenced about a 17% survival rate.