Self-delivering RNA interference (sd-rxRNA®)

RNA interference (RNAi) is a naturally occurring process by which a particular mRNA can be destroyed before it is translated into protein.

The process of RNAi can be artificially induced by introducing a small double-stranded fragment of RNA that corresponds to a particular mRNA into a cell. A protein complex within the cell called RISC (RNA-Induced Silencing Complex) recognizes this double-stranded RNA fragment and uses one strand, the guide strand, to bind to and destroy its corresponding cellular mRNA target. If the mRNA is destroyed in this way, the encoded protein cannot be made. Thus, RNAi provides a way to potentially block the expression of specific proteins.

Since the overexpression of certain proteins plays a role in many diseases, sd-rxRNA® ability to inhibit gene expression may reduce the translation of particular proteins and exert a therapeutic effect, providing a potentially powerful tool to treat neurodegenerative diseases.

sd-rxRNA®: Hybrid Oligonucleotide Structure

The sd-rxRNA® technology, in-licensed from RXi Pharmaceuticals, leverages an innovative approach in which drug-like properties built into the RNAi compound itself allow delivery of sd-rxRNA oligonucleotides to cells and tissues.
Proprietary sd-rxRNA® compounds combine features of RNAi and Antisense technologies

Traditional, single-stranded antisense compounds have favorable tissue distribution and cellular uptake properties.  However, they do not have the intracellular potency that is a hallmark of double-stranded RNAi compounds.  Conversely, the duplex structure and hydrophilic character of traditional RNAi compounds results in poor tissue distribution and cellular uptake.  Combining the best properties of both technologies, sd-rxRNA has a single-stranded phosphorothioate region, a short duplex region, and contains a variety of nuclease-stabilizing and lipophilic chemical modifications.

The combination of these features allows sd-rxRNA to achieve efficient spontaneous cellular uptake and potent, long-lasting intracellular activity. These compounds are designed for therapeutic use and have drug-like properties, such as high potency, target specificity, serum stability, reduced immune response activation, and efficient cellular uptake.

sd-rxRNA® targeting Cupper/Zinc Superoxide Dismutase (SOD1)

The sd-rxRNA® compounds targeting SOD1 coding gene interfere with translation of SOD1 protein blocking its expression and potentially preventing the production of defective (misfolded) SOD1 observed in ALS.

Treatment of rat spinal cord with fluorescent-labeled sd-rxRNA (DY547, red in picture) targeting SOD1 results in efficient and diffuse cellular uptake.  All spinal cord sections internalize sd-rxRNA compounds uniformly and efficiently.  Enhanced compounds’ penetration and distribution was observed in the brain and spinal cord.

SOD1-targeting sd-rxRNA may have disease-modifying therapeutic effects in ALS and other diseases where SOD1 protein deficit is involved.