In medical research, it is sometimes difficult to tell whether the proteins involved are cops or robbers.
One recent example is inclusion bodies, which were long thought to contribute to the pathology of Huntington's disease. More detailed studies showed that inclusion bodies actually play a protective role by sequestering a mutant protein.
Along the same lines, research published in the January 2005 issue of the Journal of Clinical Investigation promotes the adenosine A1 receptor, which has been the target of inhibition in asthma treatment, as actually having beneficial effects. The paper is titled "A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury," and authored by scientists from the University of Texas Health Science Center at Houston Medical School and the National Institute of Diabetes and Digestive and Kidney Diseases.
A previous clinical study investigated the use of an adenosine A1 receptor antagonist to treat asthma, but was discontinued after Phase IIa. The drug's developer, Epigenesis Pharmaceuticals, of Cranbury, N.J., said that "while promising results were observed in mild asthmatic patients, the effect was not generalized to patients on inhaled corticosteroids." However, the research published now suggests that the A1 receptor actually has anti-inflammatory effects.
The scientists studied the contributions of the adenosine A1 receptor to lung pathology in chronic asthma and chronic obstructive pulmonary disorder (COPD). They used a mouse deficient in adenosine deaminase (ADA) for their studies; such mice have elevated levels of adenosine, which they cannot metabolize, and show symptoms of pulmonary injury that resemble chronic asthma, as well as COPD. Adenosine, a molecule that signals cellular stress, is increased in the lungs of asthmatics, and its levels correlate with the severity of inflammation. Adenosine can have both pro- and anti-inflammatory effects, depending on which receptors it activates. For the work reported in the paper, the scientists knocked out the adenosine A1 receptors in ADA-deficient mice, creating a double knockout.
Transcripts of the adenosine A1 receptor were elevated in several cell types in the lungs of ADA-deficient mice, including alveolar macrophages, a cell type within the lungs that destroys invaders - everything from microbes to dust - and is known to play a major role in asthma.
Double knockouts had worse lung inflammation than controls, while mice with normal levels of adenosine remained unaffected by knocking out the A1 receptor. Both mucus and inflammatory chemokine production was increased in double knockouts, and alveoli (the finest branches of the lung, where gas exchange with the blood takes place) were pathologically enlarged.
Though the results demonstrate an anti-inflammatory role for the adenosine A1 receptor, the authors cautioned that "it is less clear whether this implies clinical benefit from the use of A1AR agonist in the treatment of pulmonary disorders. The A1AR has a high affinity for adenosine,and adenosine levels are elevated in the lungs of asthmatics." That implies that the interaction between adenosine and its A1 receptor might be at ceiling under clinically relevant circumstances.
New Immunoglobulin E Inhibitor In Development
The acute phase of asthma also is the subject of ongoing research. One area of interest is the development of immunoglobulin E (IgE) inhibitors. IgE is produced by an interplay of B and T cells after allergen exposure and can link allergens to mast cells. When such cross-linking occurs, the mast cells release inflammation-causing chemicals that can trigger an asthmatic attack.
South San Francisco-based Genentech Inc.'s Xolair (omalizumab) is an injectable antibody approved by the FDA in 2003. Xolair targets IgE, and interest in the development of further IgE inhibitors has been strong. In the Dec. 16, 2004, issue of the Journal of Medicinal Chemistry, researchers from Avanir Pharmaceuticals Inc., of San Diego, published data on a new series of small-molecule IgE inhibitors. The compounds were identified through a screening program, and chemical modifications led to an orally active lead compound, AVP 13358. In a mouse model of asthma, AVP 13358 reduced serum IgE levels, suppressed IgE receptors and interleukin receptors on B cells, and affected T helper 2 (Th2) cytokines. The scientists said that AVP 13358 exerts its effects by acting on the Golgi apparatus.
AVP 13358 is under active commercial development by Avanir. In May, the company announced that a Phase I trial had shown that the drug was "well tolerated" after oral administration, and described the compound's pharmacokinetic profile as "encouraging." The compound is in a second Phase I trial designed to assess multiple rising doses. In June, the U.S. Patent and Trademark Office granted Avanir a patent on "Benzimidazole Compounds for Modulating IgE and Inhibiting Cellular Proliferation," which covers the compound family, as well as a method of treatment, pharmaceutical composition and method of preparation for AVP 13358 and its active metabolite.