RNA Blockers Are Promising Alport Syndrome Therapy, Review Reports

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by Magdalena Kegel |

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Regulus Therapeutics and Sanofi-Genzyme are among companies working on Alport syndrome therapies that can block RNA molecules’ actions.

RG-012 is a man-made version of naturally occurring oligonucleotides, or RNA molecules that help regulate gene activity. The synthetic version, called antisense oligonucleotides, binds to RNA, preventing it from functioning normally.

But what are antisense drugs? And what challenges do drug developers face when turning to this class of therapies?

Researchers at the University of Texas Southwestern Medical Center looked into the complexities of developing the drugs in an article in the journal Nucleic Acids Research. They titled the piece “Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs.”

RNA molecules are middlemen in the process of producing protein from DNA, the team explained. They also serve other functions in cells. This means scientists may be able to use them to develop treatments for kidney diseases like Alport.

Put simply, RNAs are single chains of building blocks similar to the blocks that make up DNA. Scientists have learned that they can create synthetic chains of RNA building blocks that match naturally occurring sequences. These so-called complementary oligonucleotides will bind only to the stretch of RNA they mimic.

But even small oligonucleotides are huge molecules compared with the small compounds used in traditional drugs. To get such a large molecule into the cell where it is needed has been challenging.

Not only are they large, but at first glance their chemical properties appear to make them poor prospects for passing through the membranes that surround cells.

For decades, researchers have been trying to modify the molecules’ chemical structure so they are more potent against diseases, cause fewer side effects, and can enter cells easier.

In recent years, the work has begun paying off. The U.S. Food and Drug administration has approved several antisense drugs, and others are in late-stage clinical trials.

There are several classes of antisense treatments, each targeting different types of RNA molecules.  Alport syndrome researchers are focusing on ones that target microRNAs.

Studies have shown that a microRNA known as miR-21 drives Alport patients’ kidney scarring.

Regulus seized on the finding to develop RG-012, which binds to miR-21. In mouse models, the treatment preventing scarring, or fibrosis, and increased the animals’ survival by up to 50 percent.

Regulus is testing the therapy in a Phase 2 trial. The HERA (NCT02855268) study is comparing the treatment’s effectiveness against Alport syndrome with that of a placebo.

Meanwhile, Regulus is working on a Phase 1/2 trial to explore the drug’s properties in the body. It will use kidney biopsies for its analysis.

The studies, expected to be completed by mid-2018, may indicate whether RNA antisense oligonucleotides are a good way to treat Alport disease.


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