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Research Suggests siRNAs Treat Macular Degeneration Via General Immune Response

NEW YORK (GenomeWeb News) – New research indicates that siRNA-based treatments for age-related macular degeneration do not specifically target key genes as previously believed. Instead, the authors say, they work by a more general mechanism, stimulating the immune system, which then attacks the offending cells.

An international group of researchers tested a host of non-specific siRNAs and found that these all suppressed the blood vessel growth associated with macular degeneration just as well — in mice, at least — as those designed for treating the condition. That’s because the molecules don’t work by knocking down gene expression but by stimulating an immune system receptor. The results, published online today in the journal Nature, may have implications not only for macular degeneration treatments, but also for siRNA-based therapeutics in general.

“siRNAs, including those used in clinical trials, do not enter cells or trigger RNAi,” senior author Jayakrishna Ambati, an ophthalmology and physiology researcher at the University of Kentucky, said in a statement. “Rather, we found that they generically, regardless of their sequence or target, bind a receptor known as TLR3 on cell surfaces and block blood vessel growth in the eye, skin, and a variety of other organs.”

In its advanced stages, age-related macular degeneration can cause blindness when too many blood vessels grow in the eye’s retina, interfering with its proper function — a condition called choroidal neovascularization (CNV).  

siRNA treatments developed to combat the condition have shown promising results in mice, despite the fact that mammalian cells don’t typically take up so-called ‘naked’ RNA. Indeed, two siRNAs — VEGFA siRNA and VEGFR1 siRNA, which target a protein called vascular endothelial growth factor-A and its receptor, respectively — seem to suppress laser-injury induced CNV in mice.

The molecules are designed to knock down the retinal blood vessel cell growth genes. But, Ambati and his team argue, that’s not how they treat CNV.

The researchers injected a handful of other synthetic, duplex siRNAs, 21 nucleotides or longer, into the vitreous humor of mice. Not only were the siRNAs not designed to interact with genes involved in blood vessel growth, many of them were targeted to non-ocular, non-mammalian, or non-expressed genes.

Even so, the authors reported, the siRNAs all suppressed CNV in a dose-dependent manner. So did an siRNA with a random sequence and chemical modifications that prohibit it from being incorporated into the RNA-induced silencing complex.

When they followed one siRNA linked to a fluorescent probe, the authors saw that it did not enter the human or mouse cells tested unless attached to a cholesterol molecule.

Instead, naked siRNAs seemed to suppress CNV by interacting with the toll-like receptor 3, a cell surface receptor that senses long, double-stranded, viral RNA and kick starts the innate immune system. The siRNAs did not suppress CNV in mice engineered to lack the receptor. Neither were they effective in mice lacking proteins downstream of TLR3 signaling.

Similarly, the authors report, the targeted, therapeutic siRNAs were only effective when the cell surface receptor was present. For instance, the VEGFR1 siRNA, which targets vascular endothelial growth factor-A’s receptor, could enter cells and knock down VEGFR1 when it was fused to cholesterol. But it only suppressed CNV when TLR3 was present in cells.

Preliminary experiments also indicated that human endothelial cells from individuals with TLR3 polymorphisms that decrease TLR3 expression and function were differentially affected by non-specific siRNAs.

Overall, the researchers concluded, the evidence suggests that siRNAs mitigate CNV through a general immune response, as opposed to a specific mechanism that decreases angiogenesis gene expression. These results, they said, suggest it is possible to develop CNV treatments from generic dsRNAs. But they also indicate that there are additional factors to consider when evaluating the potential side effects of these — and perhaps other — siRNA therapeutics.

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