Now, here's a paradox:
Anemia results from the loss of red blood cells, which ferry oxygen-carrying iron all over the body. Yet the severest forms of anemia end up overloading the body with iron it can't get rid of.
One striking example of this counter-intuitive effect is Cooley's anemia, a.k.a. thalassemia major. "Cooley's anemia is a childhood genetic disease of the blood," said molecular biologist Raymond Bergeron, who is on the faculties of medicine and medicinal chemistry at the University of Florida, in Gainesville, and a leading authority on iron metabolism.
"You and I have four or five grams of iron on board in our bodies," Bergeron explained. "We get rid of a milligram or two a day, and take on about the same amount. We don't absorb much; we don't excrete much.
"What kids with Cooley's anemia have is a hemolytic anemia. So, their hematocrit goes down because their red cells are being lysed. And when a red blood cell is hemolysing, it gets processed in the spleen. That's where everything is metabolized and disposed of except the iron, because the body has no mechanism for excreting iron.
"The kids end up with a enormous amount of iron in their liver, which ultimately moves to the cardiac muscle, and — unless treated — they die of cardiac disease while still in their late teens.
"The only way to deal with this," Bergeron went on, "is to give them infusions of chelators — chemicals that bind iron and promote excretion of the metal through the kidneys and the bowel." The current therapeutic chelating agent is deferoxamine (DFO), which has been used against iron overload for the past 30 years.
Bergeron continued: "The real problem with DFO is one of patient compliance. Kids have to get this drug 12 hours a day, five days a week, via a portable infusion pump that sticks a needle syringe into their belly. When they pee in the morning, they pee orange, and everybody is happy about that, because they say, 'Wow! I'm getting rid of this iron that's going to kill me!' But then it becomes an issue of discomfort and inconvenience. You're dealing with teenagers, and they don't like to be wearing pumps.
"Many of them have a painful allergic reaction to DFO," Bergeron pointed out. "Some patients can't take it at all, so they have to go to alternative chelators, which are even more unpleasant.
"But the main trouble with DFO treatment is that it's not very efficient. It only clears five percent of the iron it should be removing from the body."
NIH Meeting Hears Of Alternative Approaches
Bergeron was one of two principal organizers of a two-day workshop last week at the National Institutes of Health, in Bethesda, Md. Its theme: "Iron: From current biochemistry to new chelator development strategies." Co-sponsors included New York-based Cooley's Anemia Foundation Inc.; Novartis Pharmaceuticals Corp., of New York; and SunPharm Corp., of Jacksonville, Fla. Bergeron is scientific consultant to SunPharm.
He reported to the workshop on "Alternative approaches to chelator development."
"We described some new orally active iron chelators that have come out of our lab," Bergeron told BioWorld Today, "which we are going to bring to the clinic, in conjunction with NIH and SunPharm.
"We also presented an intermediate solution called HBED, which is a device that will be going to the clinic very shortly. HBED works about three times as well as DFO.
"If Cooley's anemia patients had to take those infusions only one or two days per week," Bergeron observed, "those kids would be much happier. I asked patients attending that workshop if HBED would interest them. Their response was, 'Absolutely!' Another problem with deferoxamine is that it causes an inflammatory response. So if you stick it in the belly, they get this huge, red, hot, sore, sensitive area around the needle site. HBED doesn't cause that."
HBED is a chelator that's given parenterally — usually by subcutaneous or intravenous injection. "It doesn't work orally," Bergeron told his workshop audience. He has a separate, orally available compound that "functioned marvelously" in a primate model of iron overload, and checked out as non-toxic in a 30-day rodent trial.
"What we're doing now," he said, "is trying to isolate a company to go ahead and scale it up.
"This orally effective device," he recalled, "came out of a research program that was funded by NIH, and is still ongoing. They gave us $2.7 million, and this is what's unfolded from it."
The university owns Bergeron's patents and has licensed them to SunPharm, which provides his laboratory with financial support. "One main issue at this meeting was we didn't want to restrict the agenda specifically to Cooley's anemia," Bergeron said. "It turns out now that there are other diseases in which iron represents a therapeutic target.
"It's not just these [Cooley's anemia] kids who face iron-overload problems, but people who have sickle cell anemia," he added. "Because they're living longer, and require frequent blood transfusions, they're building up iron too. And then there's a third, very large population," he pointed out. "Older people getting what we call myelodysplasia. This is something we see a lot of in Florida, because it's a big retirement community. These people are developing iron overload too. It's caused basically by anemia; for which they have to get blood transfusions.
"It's difficult to convince a person who's 75 years old," Bergeron recalled, "that they ought to be walking around with a pump in their belly all week long. Our alternative scenario applies here too: Offer them a shot, or just one day of infusion, or a pill."
Cooley's Only Tip Of Iron-Overload Iceberg
"Malaria, which still remains the world's No. 1 killer, is another iron-metabolism disease," Bergeron said. "It's been demonstrated quite clearly that you could shut down Plasmodium falciparum with chelators.
"And we have just demonstrated that iron chelators are very effective, at least in animal model systems, in controlling inflammatory bowel disease." This affliction strikes more than a million Americans a year.
"At the end of the day," Bergeron concluded, "we have now discovered ways to exploit how various disease processes depend on iron. It's a critical metal. There is no life on earth without iron. Obviously, if you get rid of all iron, you're going to kill somebody. It has to be a well-aimed bullet." *