LONDON - An established heart drug may be able to slow the degeneration of retinal cells that occurs in the inherited condition retinitis pigmentosa, a study by French researchers suggests. The drug, diltiazem, is currently used to treat hypertension and angina in humans, but the new research shows that it can slow the death of retinal cells in a mouse model of retinitis pigmentosa.

Clinical trials to evaluate the effect of diltiazem on people with retinitis pigmentosa could start very soon, because the drug's toxicological and cardiac therapeutic effects already are well known. Serge Picaud, a researcher at INSERM in Strasbourg, France, called for well-controlled trials to begin as soon as possible, to avoid illicit use of diltiazem by people with retinitis pigmentosa.

Picaud, with Professor Jose Sahel and colleagues at the Universite Louis Pasteur in Strasbourg, reported their results in a paper in the October issue of Nature Medicine titled, "Retinitis pigmentosa: rod photoreceptor rescue by a calcium-channel blocker in the rd mouse."

Picaud told BioWorld International, "This study will give a lot of hope to people affected by this disease. But it will be important to have tests on humans, because if there is no benefit to humans, then we need to know."

Retinitis pigmentosa is an inherited disease that affects one birth in 4,000. Caused by many different mutations, people with the disease experience first night blindness (poor vision in dim light), followed by loss of peripheral vision (tunnel vision) and, eventually, total blindness. The age of onset of blindness varies greatly and can range from adolescence to middle age. Blindness results from loss of the retinal rod cells followed, eventually, by loss of retinal cone cells.

In recent years, researchers have been able to evaluate potential therapies for the treatment of this disease by studying the retinal degeneration rd mouse. In these mice, the degenerative process begins at the age of 8 days. They have a mutation in the gene encoding the beta-subunit of rod cyclic guanine monophosphate (cGMP) phosphodiesterase, as in some affected human families. The result is an increase in cGMP concentration, which is toxic to normal photoreceptors, although no one knows why.

When a photoreceptor cell responds to light, calcium channels in its membrane close. cGMP opens these channels. Picaud and his colleagues therefore decided to find out what happened when these channels were blocked with the calcium-blocker diltiazem.

They injected the rd mice intraperitoneally with diltiazem, beginning on postnatal day nine. When they looked at the retinae on day 25, they found that rod cells were 186 percent more numerous in treated mice than in untreated rd mice. At 36 days, rod numbers were 248 percent higher in treated mice than in controls. These differences were statistically significant.

Cone cells were 109 percent and 144 percent more plentiful on days 25 and 36, respectively, in treated mice than in control rd mice. This difference, too, was statistically significant.

To find out if the cells that were surviving were functional, the group carried out electroretinograms (ERGs), a measure of the physiological characteristics of the photoreceptors. Normally, in rd mice, the ERG begins to fade on day 12 and is gone completely by day 24. Yet by day 25, ERG signals were still detectable in rd mice treated by diltiazem, whereas they had disappeared from control rd mice. At 36 days, four out of 10 treated mice still had ERG signals in both eyes.

Picaud and his colleagues concluded in their paper, "Although the rescue effect was seen for only a few weeks, which may seem limited compared with the human life span, this is very important given the time scale of photoreceptor degeneration in the rd mouse, in which this process is almost complete in a two-week period. As the time scale of photoreceptor degeneration can extend over years and even decades in humans, this pharmacological approach might offer the possibility to postpone considerably the occurrence of blindness for people affected by retinitis pigmentosa."

Sahel, who is an ophthalmologist as well as head of the research group, suggests clinical trials in humans initially should be restricted to those patients with mutations in the phosphodiesterase gene, or other proteins involved in the phototransduction cascade. The group is urging people to wait for the results of well-controlled human tests.

Next, Picaud and his colleagues plan to carry out further studies to confirm diltiazem's protective effect, and hope to discover the molecular mechanism by which it works. It may be possible, Picaud said, to find an even better drug to treat this disease.