RNA interference (RNAi) holds great potential in its ability to treat disease at the genetic level, targeting the root of the disorder. It is a natural, selective process for turning off genes.
It is triggered by short interfering RNA (siRNA) molecules that engage a group of cellular proteins, known as RISC (RNA induced silencing complex). The RISC guides the siRNA to its target messenger RNA (mRNA, the messenger between DNA and proteins) by complementary base pairing for the targeted break-up of the mRNA thus halting protein expression or viral replication. The RISC-siRNA-complex binds and cleaves multiple mRNA molecules in a catalytic fashion.
In the study, published in Nature Biotechnology, Sirna used short interfering RNA (siRNA) at 1, 3 and 5 mg/kg together with encapsulation and delivery technology provided by Protiva Biotherapeutics.
The siRNA formulation, targeting HBV, was administered by standard intravenous injection to mice carrying replicating HBV. Three therapeutically relevant doses of 1, 3, or 5 mg/kg resulted in up to a 95 per cent dose dependent reduction in serum HBV DNA levels. A similar reduction was observed in Hepatitis B Surface Antigen protein levels. The anti-viral activity persisted for at least seven days.
The researchers discovered that this unprecedented efficacy correlates with a significantly longer circulation time of siRNAs in blood plasma and residence time in the liver compared to unmodified and non-encapsulated siRNAs.
Importantly, Sirna modified and optimised the siRNAs used in the study to abrogate the induction of serum interferon-alpha (IFN-alpha) and inflammatory cytokines (IL-6, TNF-alpha) thereby further demonstrating Sirna's capability to chemically modify RNAi-based therapeutics to modulate cellular responses.
"This is the second study published by Sirna scientists that validates the efficacy of chemically optimised siRNAs in vivo. We plan to initiate hepatitis C clinical trials next year," said Sirna senior vice president and chief scientific officer, Barry Polisky.
Despite these encouraging results, the study was quick to point out that the development of siRNAs as therapeutic agents would require improvements in both the stability of siRNAs1-3 and the efficiency and specificity of tissue-targeted delivery in vivo.
"We previously reported on a novel combination of chemical modifications that dramatically increase the in vivo stability of siRNA3," the researchers noted. "In an in vivo mouse model of HBV replication, stabilised siRNAs targeted to the HBV RNA (HBV263M) were dosed at 30 mg/kg three times per day resulting in a 90 per cent reduction in serum HBV DNA."
RNA interference-based therapeutics has potentially significant advantages over traditional approaches to treating diseases. For example, its broad applicability means diseases for which an abnormal gene function can be identified as a cause or as an essential contributing factor are potentially treatable with RNA interference-based drugs.
In addition, RNAi's therapeutic precision means that some of the side effects associated with traditional drugs may be reduced or avoided by using RNA interference-based drugs designed to inhibit expression of only a disease-associated and targeted gene and not interfere with other genes in the body.
Compared to most drugs that only temporarily prevent targeted protein function, RNA interference-based drugs are designed to destroy the target RNA and therefore stop the associated undesirable protein production required for disease progression.
Sirna initiated primate studies in its hepatitis C program in June 2005 and expects to commence phase I human clinical trials in 2006.