In principle, RNA interference is the next big thing in medicine. In practice, though it's mostly been another matter, due in large part to delivery issues.

siRNAs (short or small interfering RNAs), which inhibit protein expression by destroying messenger RNA with a sequence that is complementary to that of the siRNA, can specifically target just about any gene.

"Not every disease gene is targetable" University of California at San Diego's Steven Dowdy told BioWorld Today. "But a realistic number is probably 70 percent" – a percentage that would greatly extend the druggable genome, which is currently heavily biased toward a few types of proteins such as of G-protein coupled receptors and kinases.

With a few notable exceptions, such as the liver and the eye, to date, siRNAs have been extremely hard to get into the cells where they need to be.

Now, Dowdy and his colleagues have developed a chemical modification for siRNAs that allowed them to stay inconspicuous in the bloodstream as well as cross cell membranes. The technology, which has been licensed to San Diego biotechnology company Solstice Biologics LLC, could extend RNA interference far beyond its current reach.

The team published its findings in the Nov. 17, 2014, online edition of Nature Biotechnology.

For all its targeting versatility, Dowdy said, siRNA is "a terrible molecule from a drug point of view."

The reason is that for both the immune system as a whole and the individual cell, keeping foreign DNA and RNA out is a top priority.

In the bloodstream, "the body is always looking out" for foreign invaders, Solstice CSO Curt Bradshaw told BioWorld Today. So siRNA is seen as the likely calling card of an infection and rapidly degraded.

Additionally, cell membranes are all but impermeable to the highly negatively charged phosphates that make up the backbone of nucleic acids. A typical siRNA molecule has 40 phosphate groups in its backbone, which makes it an almost complete nonstarter from a drug delivery point of view.

The frustrations of delivering siRNA led to a biopharma exodus from the field a few years back. And while there have been some attempts at a return, delivery remains a vexing issue for siRNA.

In the work now described in Nature Biotechnology, Dowdy and his team neutralized the phosphate charges by attaching chemical side chains, creating what they termed short interfering ribonucleic neutrals (siRNNs). The siRNNs are prodrugs that are cut by cellular enzymes and turned into siRNAs once they have entered cells. But "outside of cells, that RNN doesn't look like an invading nucleic acid."

"And it's not just that we neutralized the phosphates,"Dowdy added. "There's a whole list of attributes that this contributes to," including increased stability in the bloodstream, that makes siRNNs more drug-like than siRNAs.

Dowdy and his team compared their siRNNs to state-of-the-art siRNAs targeted, in each case, to the liver, and found that siRNNs led to greater knockdown of target genes than siRNAs.

One place where siRNA delivery has been successful is the liver, where siRNAs conjugated to sugars can be taken up by liver cells. Despite being neutrally charged, siRNNs, like siRNAs, will not diffuse across cell membranes, but need to be targeted to specific cell types by ligands that can bind to receptors on cell surfaces and deliver the molecules via endocytosis. The reason siRNA delivery to the liver has been successful is because the liver possesses very large numbers of very rapidly cycling receptors that can be targeted via the carbohydrate GalNAc.

Because siRNNs are more stable in the bloodstream, Dowdy and his colleagues said they believe they will be able to conjugate them to other targeting domains that can deliver the prodrug to cells with fewer receptors, or receptors that are taken up by the cells more slowly.

"The future, for us, is to add different targeting domains," Dowdy said. His academic laboratory is looking for targeting domains that will allow them to deliver siRNNs to prostate cancer cells.

Solstice Biologics is the exclusive licensee of the siRNN technology. Given its broad applicability, Solstice CEO Lou Tartaglia told BioWorld Today, "we're going to bite off more than we can chew" in terms of possible drug development programs.

The company plans to use siRNN technology for its own development programs in what Tartaglia called "biotech-friendly indications" such as orphan diseases and genetically defined diseases.

But Tartaglia has also been in discussions with pharma and large biotech companies to learn which cell types should be the top priority.

Based on a combination of high interest and low-hanging fruit, the company is prioritizing the development of targeting methods for immune, lung, kidney and muscle cells.

One of the strengths of siRNNs, Dowdy said, is that once a targeting domain for a specific cell type has been developed, delivering different RNAi sequences to that cell type is, if not exactly simple, then still a very clear-cut process compared to targeting a protein via different small molecules or antibodies. In practice, this means that going after diseases that are themselves evolving – whether infectious diseases or cancer – is a less daunting prospect with RNA interference.

Small molecules and antibodies "go after a single target," Dowdy said. "Once that target mutates, that drug is done. But for siRNN, it's 'point mutation – so what?'

"We can synthesize an RNN [to the mutated sequence], start it on Monday and have it in an animal by Friday. Undergraduates can do this," he said.

Those new sequences will still, of course, take considerably longer than a week to get FDA approval. But Dowdy said that if the technology gains broad traction, trials, too, will become simpler over time, because of the greater similarity of one siRNN to the next as compared to small molecules.

Ultimately, he said, there might be a broad range of siRNNs targeting specific mutations available off the shelf.

"That's the over the horizon and the rosy glasses view. . . . We haven't put [siRNNs] into primates or humans yet," Dowdy acknowledged. "It's going to take a long time to get to that point. But I'm an optimist. . . . That's where it's going to go."