The research was set up to address the activity of chemically modified short interfering RNA (siRNA) in a mouse model of hepatitis B virus replication. The data provides in vivo validation of chemical modifications of siRNAs and the distinct differences between modified and unmodified molecules necessary for therapeutic relevance.
The studies show that chemically modified siRNAs provide greater stability and efficacy, improving their delivery compared to non-modified siRNAs. When delivered by intravenous injection, a clinically relevant method of administration, the siRNAs reduced hepatitis B virus (HBV) replication in rodents.
To initially assess activity of the stabilized siRNAs in vivo, an HBV vector-based model was employed in which the siRNA and the HBV vector were co-delivered via high volume tail vein injection. A significant decrease in levels of serum HBV DNA and HBsAg, as well as liver HBV RNA, were observed in the siRNA treated groups compared to controls.
The observed decrease in serum HBV DNA was greater in mice treated with a modified siRNA compared to an unmodified siRNA indicating the value of chemical modification in therapeutic applications of siRNA. Progressing beyond high volume tail vein injection in subsequent experiments, standard systemic intravenous dosing of modified siRNA, resulted in a reduction of serum HBV DNA levels while no activity was observed with unmodified siRNA.
These experiments establish the strong impact that siRNAs can have on the extent of HBV infection and underscore the importance of modification of siRNA against nuclease degradation. The siRNAs used in these experiments were fully chemically modified in that no standard ribose sugars were present in the structure. Sirna believes the data proves that the company’s invention of these “no ribose” forms has significant therapeutic potential.