By David N. Leff
A basketball player dropped dead on the court the other day. The cause was asthma — in other words, strangulation.
Like garroting, a pillow pressed down over the face, a plastic bag over the head, or drowning, asthma cuts off, or cuts down, the intake of air to the lungs. To be sure, few of the 10 million Americans afflicted with asthma die of the disease, but between 1982 and 1992 its death rate did increase by 25 percent and the number of cases by 42 percent. Its severity keeps going up, too.
A person knows that he or she is suffering an asthmatic attack when breathing becomes more and more labored. What breath there is comes out in squeaking, musical, puffing or whistling wheezes. The chest feels tight; coughing is common.
At the root of this airway constriction is inflammation of the bronchial tubes, which divide and subdivide like the limbs, branches, twigs and leaves of a tree, as they spread in the lungs to inhale the air's oxygen and exhale carbon dioxide.
That pulmonary inflammation, which swells, and thus narrows, the bronchial airways, is nature's way of turning loose the body's immune system to fight off foreign attacks on the breathing apparatus. But as asthmatics know well, more things than allergenic dusts, pollens, dander, pathogens and cigarette smoke can unleash the battalions of lung-targeting immune-system factors that trigger asthma's acute hypersensitivity.
A common cold can do it. So can cold weather, anxiety or — as in the case of that basketball player — exercise.
One notorious culprit is immunoglobulin E; another, the release of cytokine growth factors and suchlike mediators of acute hypersensitivity from mast cells, which are plentiful around lungs and airways.
But not everyone is vulnerable to these slings and arrows of outrageous asthma. There are genetic factors that decide who is highly susceptible to airway constriction (hyperresponsive), and who is resistant, not affected at all (hyporesponsive). This isn't an either/or proposition; the syndrome is a continuous variable in human and mammalian populations — including mice.
"No one has concretely defined the mechanism of susceptibility-resistance to asthma," observed molecular geneticist Roy Levitt. "It's a complex inherited pattern, with multiple genes involved. So it won't be a simple dominant or recessive."
He added: "That's what turned a number of us geneticists on 20 or 25 years ago, to begin looking at genetics as an important factor in asthma."
Levitt, then at Johns Hopkins University, reported two years ago on locating, to a major region on human chromosome 5, a gene or genes for hyperresponsiveness.
Mouse Responsiveness Measures Up
In January of 1996, he joined Magainin Pharmaceuticals, Inc., of Plymouth Meeting, Pa., as director of the company's institute of molecular medicine. "Hopkins," he recalled, "released the intellectual property to me when I left. After all, it was mouse data."
Now he reports new mouse data, in today's Proceedings of the National Academy of Sciences (PNAS), dated Nov. 25, 1997. Its title: "Interleukin 9: A candidate gene for asthma."
To reach this discovery, Levitt recruited 150 recombinant, inbred mice from 26 distinct murine strains. They represented an animal model for that human continuum of risk-factor sensitivity. "The whole lot was from different genetic backgrounds," Levitt told BioWorld Today, "and distinguished the hyperresponsiveness from the hypo."
That is, he and his co-authors didn't make knockout or transgenic mice, but "simply took varied populations and identified, as one would in a human series, which are susceptible to asthma. We had found that in many respects, mice resemble the human condition, so we set out to find the murine genes,which might provide insights to the human variability."
As in clinical diagnosis of asthma susceptibility, the team gave the mice a bronchoconstrictor, which narrowed their airways to asthma-like semi-closure. Then they evaluated that degree of constriction in each animal.
"We looked at which were high responders and which low." levitt recounted, "then, by standard genomic techniques, we used those individuals to map the corresponding gene. And that mapping, "he continued, "provided us with a specific murine, chromosomal region that corresponded nicely with what we had seen in humans in our prior study."
He noted "an important point: It narrowed the region we had to look at in the human chromsome 5, which was quite large. In the mouse it was a relatively small locus, where by sorting through a few genes we found interleukin-9 [IL-9]. It showed a genetic alteration that produced biological variability in that gene, relating back to bronchial responsiveness."
Their candidate gene sits on mouse chromosome 13, which corresponds to the long arm of human chromosome 5.
Interleukin-9: Trigger For Anti-Asthma Therapeutics
IL-9, Levitt pointed out, "has not been studied nearly as well as IL-2, IL-4 or IL-5, and many other cytokines. Actually, IL-9 is known to play an important role in many aspects of the immune inflammatory pathway related to asthma. It turns out to be a helper T cell growth factor, associated with the allergic immune response."
But that's not all. "IL-9," Levitt went on, "is also a mast cell growth factor, up-regulating, for example, IgE high-affinity receptors, as well as proteases."
Some of those enzymes, he pointed out, "are in fact targets for pharmaceutical development." He mentioned that Arris Pharmaceutical Corp., of South San Francisco, together with Bayer Corp., of Pittsburgh, Pa., "is developing a small molecule to antagonize tryptase activity."
As for Maigainin, Levitt allowed, "We have small-molecule targets as well that we're developing. We're trying to do that," he said, "in collaboration with a big-pharma partner, who we can't name yet, which will facilitate and expedite the development of new therapies."
He noted that his institute has "other papers in process, which we expect to publish soon. They describe more genes in the interleukin-9 pathway and their role in asthma.
"We believe," Levitt continued, "that our publication in today's PNAS will excite people to begin to investigate this pathway, as to how it functions to turn the antigen responsiveness gain up or down, like the volume control on a TV set. This is the cornerstone of our program," he concluded, "and as people verify our data and build on it, they will provide new therapeutic approaches to treat the root causes of asthma, not just its symptoms." *