Overview of eiRNA
Advantages of eiRNA
Nucleonics'
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Nucleonics has focused on developing its proprietary variant of RNAi technology called "expressed, interfering RNA" (eiRNA) because it has several major advantages over direct or synthetic RNAi approaches. With eiRNA therapeutics, the drug consists of a DNA vector which encodes the double-stranded RNA molecules. When the DNA vector is administered to a cell or organism it will cause the cell to generate multiple copies of the desired RNAi molecules inside the cell and over an extended period of time, thereby amplifying the RNAi mechanism. In addition, Nucleonics' eiRNA technology favors the use of plasmid DNA vectors instead of the virus-based vectors traditionally used in "gene therapy" approaches. Plasmid DNA is a stable drug format that benefits from well characterized manufacturing methods, storage techniques, regulatory requirements and a favorable safety profile based on earlier DNA vaccine clinical trials.
Specific benefits provided by Nucleonics' eiRNA technology include the following:
  • One eiRNA molecule entering the nucleus of a cell will produce thousands of copies of RNAi molecules, allowing for sustained therapeutic responses vs. the repeat administration expected to be required of direct or synthetic RNAi drugs that will have an inherently shorter molecular half-life.
  • One eiRNA molecule can encode multiple (4 or more) short RNAi molecules. This is critical in the design of effective antiviral therapeutics where more than one RNAi must be delivered to circumvent development of viral resistance from viral mutations that reconfigure the site of molecular intervention.
  • eiRNA is DNA based and DNA molecules are inherently more stable in the body and on the pharmacy shelf than RNA molecules. Directly-administered RNAi molecules must be chemically modified to achieve stability in blood or tissues, and these modifications can affect the RNAi potency and toxicity profile of synthetic RNA molecules.
  • eiRNA is DNA based and cellular uptake of DNA typically does not induce the undesired, non-specific cellular stress response elicited by direct double-stranded RNA.
Advantages of Plasmid DNA vs. Viral Vectors
The field of gene therapy has traditionally relied upon using recombinant viral vectors to shuttle genetic information into cells. While viral infection is a naturally efficient means for introducing nucleic acids into a cell, and viral vectors developed for human gene therapy are designed to avoid the pathology induced by a natural infection, the engineered viral vectors nevertheless alter cellular metabolism and may induce undesirable immune responses. Any metabolic alterations and immune responses induced by viral vectors can be directly harmful to the host and can actually work against the desired therapeutic effect from the viral vector's genetic payload. Accordingly, the safety and usefulness of viral vectors has thus far been significantly impaired by these drawbacks.
In contrast, the field of DNA vaccines has generally employed non-viral, plasmid vectors to safely administer genes into human subjects, primarily by injection into muscle tissue. Nucleonics has adapted and improved these expression systems for use in systemic, intravenous delivery of eiRNA therapeutics to animal tissues. The company has also demonstrated intraperitoneal, intraturmoral and subcutaneous administration of plasmid DNA vectors using its proprietary delivery technologies and formulation techniques. Administration of plasmid based eiRNA vectors reduces the major safety concerns present with viral vectors because there is no integration of plasmid DNA into the host cell and no delivery of any viral protein or protein-coding DNA that might trigger undesired immune responses.