An experimental therapy to treat the eye disease macular degeneration might actually cause blindness in some patients, according to a study published today.
The treatment uses so-called 'small interfering RNA' molecules (siRNAs) to try and slow down degeneration in the area of the retina that is responsible for central vision. This type of degeneration is the leading cause of vision loss in people over the age of 50 in the United States.
The warning that siRNAs might cause more harm than good in the eye has been dismissed by one of the companies testing the therapy. But scientists are concerned because there are no published studies that have tested whether the side-effect is occurring in ongoing human trials.
“The concern is whether in trying to cure one form of macular degeneration, you are causing the other form.”
Kang Zhang
University of California, San Diego
"This study really poses serious concerns about whether siRNAs can cause damage, although this will need to be tested further," says retina specialist David M. Brown of the Methodist Hospital in Houston, Texas, who was not involved in the work.
The study, led by Kang Zhang of the University of California, San Diego, adds an extra layer of complexity to the phenomenon of RNA interference, a process in which small pieces of genetic material, such as siRNAs, trigger cells to shut down or silence the activity of certain genes. Two companies — OPKO Health of Miami, Florida, and Allergan of Irvine, California — are testing whether siRNAs could slow the progression of the 'wet' version of macular degeneration, where abnormal blood-vessel growth damages cells in the retina.
The companies are injecting patients' eyes with siRNAs that target a gene called vascular endothelial growth factor (VEGF), which triggers the growth of blood vessels.
But in March, University of Kentucky researcher Jayakrishna Ambati reported that VEGF could be silenced by any siRNAs injected into the eye — not just those targeting VEGF1. Ambati found that the siRNAs activated a protein called toll-like receptor 3 (TLR3), a so-called 'innate immunity' molecule that causes cells to commit suicide when they are infiltrated by foreign RNA.
Zhang wondered whether that suicide response might also be involved in the 'dry' form of macular degeneration, which can lead to geographic atrophy — vision loss caused by death of the photoreceptor cells in the eye. There is no treatment for this condition.
Danger gene
Zhang's team compared TLR3 genes in 600 patients with geographic atrophy to TLR3 genes in patients with other forms of macular degeneration, or with no eye problems. His team reports in the New England Journal of Medicine that a mutation in TLR3 protects some patients from developing geographic atrophy2.
Zhang estimates that patients with the protective form of the TLR3 gene have a 30-70% lower risk of developing geographic atrophy than those without the mutation, depending on how many copies of the mutation they carry. In further studies, the team then found that human eye cells without the protective TLR3 mutation were far more likely to die in response to RNA triggers than cells with the mutation. Mice lacking TLR3 entirely were also less likely to develop syptoms similar to geographic atrophy when an RNA trigger was injected into their eyes.
These findings raise concerns about the ongoing wet macular degeneration trials, in which siRNAs are injected into patients' eyes, say Zhang and other scientists. They are worried that the injections may cause geographic atrophy by activating TLR3, and that patients without the protective TLR3 utation will be especially vulnerable to this side effect.
"The concern is whether in trying to cure one form of macular degeneration, you are causing the other form," Zhang says.
Sam Reich, executive vice president of opthalmics at OPKO, disagrees that there is serious cause for concern about RNA interference in the eye. He points out that OPKO has tested its drug in 400 patients with wet macular degeneration, and that 200 of those patients have been followed for at least two years without major side effects. In addition, Reich says, two other companies have tested small RNAs in the eyes of 600 more patients with no ill effects.
"There is an enormous body of papers supporting the potency, specificity and efficacy of small RNAs that totally dwarfs this paper," Reich says.
Yet Brown suggests that the ongoing studies may not have included enough patients with both versions of the TLR3 gene to notice an effect. He says it would make sense for OPKO and other companies to test which version of the TLR3 gene their patients carry – something OPKO, at least, is not doing. "But I think that is the most prudent thing they could do," Brown says.
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References
- et al. Nature 452, 591-597 (2008).
- et al. New England Journal of Medicine doi:10.1056/nejmoa0802437 (2008).