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RNAi: Stopping the Power of Misfolded Proteins


By Staff Reports

(DGIwire) – The idea of targeted, personalized medicine has been a dream for decades—and it is now becoming a reality thanks to advances in genetics. As recently reported in an article on the website of the American Society of Mechanical Engineers (ASME), a large part of this revolution is being driven by advances in understanding RNA.

According to the article, RNA serves as a sort of messenger, carrying instructions from DNA to control protein synthesis and other activities. One particular growth area for RNA-based medicine involves RNA interference (RNAi), which is a process by which the messenger (the RNA) is stopped, inhibiting protein creation by the body’s genetic code. As the ASME article notes, it is a stop sign for DNA, and something that everyone on Earth has in their cells—regulating the amount of protein production and making sure the body does not overproduce anything it needs.

In light of this natural behavior, RNAi holds much potential for drug developers, who are working to harness the “stopping power” of this process to target specific proteins and address individual genetic risks in patients, notes the ASME article.

“There are a number of diseases where certain proteins are produced that are not the right protein,” says Dr. Geert Cauwenbergh, President and CEO of RXi Pharmaceuticals, a clinical-stage RNAi company developing therapeutics based on its proprietary self-delivering RNAi (sd-rxRNA®) platform. “That, of course, is the case in Huntington’s disease and Lou Gehrig’s disease, ALS, where there is a misfolded protein being produced, and so you don’t want that protein there.” In certain disease conditions, you may still need the protein, but not in the same amount. A good example of that is lowering certain proteins in immune cells (so called immune checkpoints), to make them less susceptible to methods cancer cells use to reduce the immune system activity.

RXi has developed a process involving ex-vivo treatment of the immune cells with siRNA molecules inhibiting expression of immune checkpoint genes. To achieve the suppression of gene activity, the compounds need to be delivered inside target cells. Commonly used methods, such as lipid-mediated transfection and electroporation, may be of low efficiency and may be associated with high cell toxicity. RXi’s self-delivering RNAi (sd-rxRNA®) technology incorporates delivery properties that allow the compounds to efficiently transfect immune cells. The technology can be combined with a variety of cell processing protocols used in clinical practice.

sd-rxRNA can be generated within a short period of time for virtually any target in the genome. RXi uses a proprietary algorithm yielding a series of sd-rxRNA compounds with high knock-down efficiency. The most active compounds can be validated within several months and selected for subsequent preclinical and clinical development. This approach provides some key advantages over combinations of immunotherapeutic treatments, such as the use of adoptive cell transfer with immune checkpoint blocking antibodies.

“I see great potential in this technology to deliver personalized treatments for a wide range of diseases, effectively relegating today’s common treatments to medical history,” Cauwenbergh adds.


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