Heart Drug May Be Effective in Fighting Form of Blindness
A widely used heart drug can sharply slow the progression of an inherited form of blindness called retinitis pigmentosa, according to experiments in mice reported today by French researchers.
This has the potential to be the first effective treatment of retinitis pigmentosa, commonly called RP, which afflicts as many as 200,000 people in the United States, according to the researchers.
The drug, called diltiazem, could be useful in about 10% of those patients with the most aggressive forms of the disorder, experts said. And because the drug has already been shown to be safe in treating heart problems, clinical trials in humans could begin early next year.
The mice used in the studies have a form of RP in which a specific genetic defect allows calcium and sodium to flow into eye cells through passageways called calcium channels, poisoning the cells. Diltiazem is a calcium-channel blocker that closes those pathways.
“It’s not surprising that it works, but it’s very exciting and could be very important,” said Dr. Richard L. Hurwitz of the Baylor College of Medicine.
The results, reported in today’s Nature Medicine, are “proof of principle” that targeting genetic defects in RP can be successful, and may thus lead to other treatments as well, added Tom Hoglund of the Foundation Fighting Blindness.
Separately, researchers at Caltech report in today’s Proceedings of the National Academy of Sciences that another heart drug--an experimental compound known as BQ788--can suppress skin cancers in mice and may have potential for treating prostate and ovarian tumors as well.
RP is actually a group of diseases, caused by as many as 100 different genetic mutations, that gradually destroy the eye’s light-sensing cells, called rods and cones. Its progression can, in some cases, be retarded slightly by administration of vitamin A, but overall there is little that physicians can do.
Dr. Serge Picaud and his colleagues at Louis Pasteur University in Strasbourg are working with an animal model called the rd (for retinal degeneration) mouse. The genetic defect in these mice is found in about 4% of humans with RP, said Michael J. Young, who studies the retina at Harvard University’s Schepens Eye Research Institute. Related genetic defects in the same pathway, he added, bring the total to about 10% of RP patients to whom the results might be applicable.
The course of the disease in the rd mice is virtually identical to that in humans, indicating that it is a good tool for studying potential treatments, said Baylor’s Hurwitz. But the disease progresses from the first stages to complete blindness in less than three weeks in the animals, compared to the years to decades it takes in humans.
Picaud and his colleagues began injecting seven mice with diltiazem when they were 9 days old, about the time rod degeneration begins. The dosage they used, on a weight-adjusted basis, was about four times as high as that used to treat humans with angina and high blood pressure.
By the time the mice were 35 days old, the treated animals had an average of 248% more rod cells and 278% more cone cells than did untreated rd mice.
Using electroretinograms, which measure the electrical output of functioning rods and cones, the team found that the treated mice retained some vision at 35 days, while the untreated animals were blind.
“If the treatment could postpone the occurrence of blindness by a few years, it would be a big achievement, but this remains to be demonstrated in humans,” Picaud told the Associated Press.
But Picaud and others cautioned against patients taking the drug at this point. For one thing, most people with RP do not know which genetic defect they carry, Hoglund said, and 90% of them would thus be exposing themselves to adverse side effects with little or no potential for benefit. Side effects can include dizziness, headaches and a slowed heartbeat.
Hoglund also cautioned that the drug has not been tested in adolescents, who would be the primary beneficiaries if it worked. In humans, the defect found in the rd mouse strikes in early adolescence and the disease progresses more rapidly than do other forms. But if the disease could be slowed in those children, he added, that would be very valuable.
The Caltech paper involves a heart drug that has not yet been approved, so human trials may be much further in the future. Biologists Paul Patterson, Ronit Lahav and Garrett Heffner began studying it after they found that the growth of melanoma tumor cells is stimulated by a naturally occurring growth factor called endothelin.
Cardiologists had previously discovered that endothelin causes arterial blood vessels to constrict, leading to high blood pressure. BQ788, which is undergoing clinical testing as a treatment for hypertension, was designed specifically to interfere with the action of endothelin.
Patterson reasoned that if endothelin was important for the growth of melanomas, BQ788 might retard that growth. In studies in mice, the team found that injection of the drug directly into tumors halted their growth and sometimes led to regression of the tumor. Perhaps more important, injection into the bloodstream halted the growth of metastases--new tumors that form when cancer cells break off from the original tumor and migrate elsewhere in the body.
“It works whether you inject it into the tumor or into the body cavity,” Patterson said. “In about half the mice, the tumors actually shrank.”
Patterson noted that ovarian and prostate cancers may also be associated with the growth-promoting effects of endothelin, so that the drug might be useful for them as well. But experts caution that many drugs shown to halt tumor growth in mice have proved much less effective in humans, so a great deal more testing of the drug will be required.
