An experimental therapy to treat the eye disease, macular degeneration, might actually cause blindness in some patients, according to a study published on Thursday has revealed.
According to Nature‘s report, the treatment uses so-called ‘small interfering Ribonucleic Acid (RNA)molecules (siRNAs), which attempts to slow down degeneration in the area of the retina that is responsible for central vision.
The warning came as scientists warned against damaging outcomes of clinical trials.
Professor of Pharmaceutics at the University of Nigeria, Nsukka, Enugu State, Michael Adikwu, warned that clinical trials must be done with utmost regard for ethics and other protective guidelines.
"At the onset, most of these trials might look promising, but when the outcomes turns out to be devastating, it is usually difficult to curtail,"
Meanwhile, 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.
Retina specialist, David M. Brown, of the Methodist Hospital, Houston, Texas, who was not involved in the work said, "This study really poses serious concerns about whether siRNAs can cause damage, although this will need to be tested further."
The study, led by Kang Zhang of the University of California, San Diego, added 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, 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’s 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 III (TLR3), a so-called ‘innate immunity’ molecule that causes cells to commit suicide, when they are infiltrated with 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.
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 reported in the New England Journal of Medicine that a mutation in TLR3 protects some patients from developing geographic atrophy.
Zhang estimated that patients with the protective form of the TLR3 gene have a 30-70 percent 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 symptoms similar to geographic atrophy when an RNA trigger was injected into their eyes.
These findings raised concerns about the ongoing wet macular degeneration trials, in which siRNAs are injected into patients’ eyes, said Zhang and other scientists. They are worried that the injections may cause geographic atrophy by activating TLR3, and that patients without the protective TLR3 mutation 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," he said.
Executive Vice President Of Opthalmics at OPKO, Sam Reich, disagreed that there is serious cause for concern about RNA interference in the eye. He pointed 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 said, 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 said.
Yet, Brown suggested that the ongoing studies may not have included enough patients with both versions of the TLR3 gene to notice any effect.
He said 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 said.
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