Researchers at Mirus Bio Corporation have developed a technique to target specific cells with a genetic "silencing switch," known as RNA interference (RNAi), which blocks the production of disease-causing proteins inside those cells.
In a first proof-of-concept demonstration, Mirus scientists targeted liver cells and switched off their ability to produce "bad" cholesterol. This delivery platform could also be used as a foundation for RNAi therapeutics to disable cancer cells, viruses, and genes that cause other metabolic diseases, among a broad range of potential applications.
Details of this breakthrough have just been published in the online Early Edition of the Proceedings of the National Academy of Sciences under the title "Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes." Mirus Bio, which was founded in 1995, specializes in nucleic acid chemistry and delivery systems for RNAi- and gene-based therapies.
"The lack of effective systemic administration has been the primary impediment to development of RNAi therapeutics for diseases affecting internal tissues and organs," says David Rozema, PhD, one of the lead authors of the study. "This new delivery platform gives us a powerful tool to reach and silence the expression of any gene we might be interested in."
The discovery of the RNAi mechanism in 1998 revolutionized scientists' ability to discover the function and role of individual genes. Its discoverers, Drs. Andrew Fire and Craig Mello, were jointly awarded the Nobel Prize in Physiology or Medicine in 2006. Researchers have been quick to recognize a wide range of potential medical applications for RNAi. Although RNAi has already been used experimentally to treat a few diseases, there has been no efficient way to target specific cells where particular diseases occur, such as in key liver cells or inside a tumour. Moreover, injected genetic material is quickly cleared from the body. Mirus researchers have overcome these problems by assembling tiny synthetic molecules, called Dynamic PolyConjugates, that shield their genetic cargo as they home in on target cells.
The Dynamic PolyConjugates' "cargo" consists of small pieces of genetic material known as small interfering RNA sequences ("siRNA"), which blocks a cell's RNA. Normally, RNA acts as a messenger, carrying the "blueprints" for making a protein from a cell's DNA (which contains the master plans) to the ribosomes (where proteins are manufactured). siRNA can prevent the blueprints from ever reaching the ribosomes, in effect "turning off" the expression of a particular gene. siRNAs occur naturally in cells, where they defend against viruses and stray genes, but they can also be genetically engineered to turn off the expression of any gene for which the sequence is known.
One stumbling block to successfully administering RNAi-based medicines has been finding a way to shield siRNA until it reaches its intracellular target. In their natural form, siRNAs are quickly cleared from the bloodstream. Even if they were to reach their intended destination, they would soon be "gobbled up" by the cell's endosomes ("eating" structures). Mirus Bio researchers have found a way to shield siRNA by attaching it to a new type of polymer that not only protects the siRNA in the bloodstream, but also enables it to break out of a cell's endosome, so it can interact with the messenger RNA. The scientists also attach a masking agent that prevents the siRNA from being recognized as foreign. Finally, targeting molecules are incorporated that preferentially attach to target cells and prevent unwanted interactions with non-target cells. The whole package is called a Dynamic PolyConjugate.
"The industry's excitement over potential therapeutic and research applications of RNA interference continues to grow. Our siRNA polyconjugate technology represents a major breakthrough in delivery, and positions us at the heart of what has become one of the most exciting medical advances of the decade," commented Russell Smestad, Mirus Bio's president. "Not only do we have a great technology, but more than a decade of work in the nucleic acid field has enabled us to build what we believe is the strongest intellectual property portfolio in the industry covering polymer-based siRNA in vivo delivery.
In addition to Dr. Rozema, the groundbreaking work on Dynamic PolyConjugates at Mirus Bio was led by Drs. David Lewis and So Wong, Mr. Darren Wakefield and Jason Klein, along with critical contributions from Drs. Jon Wolff, James Hagstrom and colleagues.
Mirus Bio Corporation is a leader in the fields of RNA interference and gene therapy, based upon its expertise in nucleic acid chemistry and delivery. The company's Dynamic PolyConjugate technology is being refined as an enabling platform for siRNA therapeutics.