Benitec combines the power of RNAi interference with the durability of expression from gene therapy delivery to permanently silence disease causing genes. This powerful combination provides a platform to create novel therapeutics for the treatment of human disease.
RNA interference (RNAi) is an evolutionarily conserved mechanism of sequence-specific gene silencing mediated by small interfering RNAs (siRNAs), which are comprised of double-stranded RNAs of approximately 21bp. A DNA directed RNAi (ddRNAi) approach relies on the use of introducing DNA templates to utilize the cells’ endogenous transcriptional machinery to produce short hairpin RNAs (shRNAs) that are then processed by the endogenous RNAi machinery into siRNAs. Once siRNA have been loaded into the RNA induced silencing complex (RISC), the corresponding antisense strand can bind to a target RNA, ultimately resulting in the loss of the messenger RNA. With no mRNA species left to be translated into proteins, the net effect of RNAi is to induce the loss of gene expression of that targeted gene.
As is the case for any nucleic acid-based drug, the ability to deliver therapeutically relevant concentrations into the appropriate target tissue continues to be the largest technical hurdle to the field of RNAi. Because ddRNAi relies upon the transcription of shRNA from DNA expression constructs instead of delivering small synthesized RNA duplexes, a wide variety of delivery tools typical of gene therapy approaches, including the use of non-replicating viral vectors, can be employed to target a wide variety of tissue types. Many viral vectors, including adeno associated virus (AAV), can result in years of expression from a single injection providing the potential to a durable therapeutic response from a one-time treatment.
Specific advantages of ddRNAi over other technologies:
- The cellular machinery inside diseased cell is harnessed to produce a self-replenishing supply of short hairpin RNAs at steady state levels
- Multiple genes, including those in different pathways, can be simultaneously silenced from the same vector
- Depending upon the size of the target gene, ddRNAi vectors can be programmed to use shRNA to knockdown the expression of the disease causing protein, while additional packaging capacity to be used to express normal copies of the same gene, thus restoring function.
- The potential for a long-term, robust response from a single injection