PHILADELPHIA, PENNSYLVANIA—RNA therapies have struggled for decades to meet expectations in fighting genetic diseases. Now, a new version, known as a spherical nucleic acid (SNA), has the field springing back to life with success in its first human trial. The general approach to RNA therapy, called antisense RNA, aims to disrupt the production of proteins related to diseases like cancer and HIV. At the American Chemical Society (ACS) meeting here last week, researchers said the trial shows that antisense SNAs are safe and hints that they may be effective in fighting psoriasis, a debilitating skin disease.
“Even showing safety data in people is a very big deal,” says Robert Langer, a chemical engineer and drug development expert at the Massachusetts Institute of Technology in Cambridge, who was not involved in the work.
When human cells activate genes, their DNA codes are translated into snippets of single-stranded RNA called messenger RNA (mRNA). This mRNA then migrates to protein factories called ribosomes, which convert the code into amino acids, the building blocks of proteins. Occasionally, diseased cells build too many copies of a useful protein, such as one called tumor necrosis factor-α (TNF-α), which overstimulates the immune system in people with psoriasis, leading to red, scaly skin lesions.
To interrupt that process, antisense RNA therapies inject cells with RNA strands that bind to specific mRNA snippets, effectively blocking them from being read by ribosomes. This removes them from circulation before they can be converted into proteins. The trouble is that traditional antisense RNA drugs usually don’t work. To date, only two antisense RNA therapies have been approved in the United States, despite decades of effort and dozens of clinical trials. Among other problems, most introduced RNA snippets get chopped up before they reach their target by enzymes that patrol the cell for foreign material.
Unlike conventional mRNAs, which are short linear sequences, SNAs are tiny spheres with 100 or so identical RNA snippets attached to a central particle, often made of fatty molecules called lipids. This allows SNAs to get into cells and prevents them from being chopped up. In theory, they should enable therapies for dozens of genetic diseases. Researchers could simply change the sequence of the RNAs bound to the central particles; each one would block production of a different target protein.
Earlier this year, Exicure, a company in Skokie, Illinois, launched an SNA trial targeting TNF-α in people with psoriasis. At the ACS meeting last week, SNA pioneer and Exicure Founder Chad Mirkin of Northwestern University, Evanston, in Illinois, told his audience that the initial trial results suggest that SNAs are safe. What’s more, there appears to be a dose-dependent response in knocking down TNF-α, which raises hopes that doctors will be able to find a curative dose. That’s still a long way from proving SNAs are an effective cure against psoriasis, Mirkin says. However, he adds, it’s a hopeful first step.
Langer notes that the SNA result marks the latest bit of positive news for the antisense field. Several companies with refined antisense approaches, including Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Moderna Therapeutics, and now Exicure, appear to be working. “RNA therapies really seem to be taking off,” Langer says. If further SNA trials prove effective, that could be good news for more than psoriasis patients. By changing the RNA code on the SNA particles, it could open a new pathway for antisense RNA therapies.