Benitec licenses RNAi delivery system
based on RNA interference (RNAi), has broadened its patent estate
by licensing a technology from Stanford University in the US that
could overcome the problems in delivering these agents as
therapeutics.
The company has gained exclusive rights to use and sublicense Stanford's so-called Minicircle DNA technology, a non-viral delivery method for Benitec's DNA-directed RNA (ddRNA) based drugs. Earlier this month, the Australian company signed its first agreement for a therapeutic based on ddRNA with Revivicor, a US company that intends to use the approach to develop transgenic pigs whose organs could be used for human transplantation.
The Minicircles approach was developed by Mark Kay, professor of paediatrics and genetics at Stanford University and a strategic consultant to Benitec.
Researchers in Kay's lab discovered that bacterial sequences present in normal plasmid DNA - the usual format for non-viral delivery of DNA into cells - cause a significant down-regulation of gene expression in animal models. Typically, a high level of transgene product is achieved shortly after DNA is delivered to targetcells, but transgene expression falls to low levels within a few weeks even though vector DNA is retained in thesecells
By stripping out these bacterial sequences, Kay and colleagues have been able to hike expression from the sequence 500-fold compared to regular plasmid DNA.
This means that DNA Minicircles coding for therapeutic ddRNA sequences will have improved expression in cells, raising the effectiveness of the approach in switching off the target gene.
"With this new technology, we have demonstrated therapeutic levels of transgene product in animal models for up to 10 months, with no toxicity from this non-integrating vector" stated Dr. Kay.
The team said it has designed a plasmid to allow for easy purification and large-scale production of Minicircles, making this a feasible vector for clinical use.
Benitec's ddRNAi approach is an alternative method to small interfering RNAi (siRNA) in inducing RNA interference, a natural cellular mechanism that selectively negates the effect of any gene by destroying messenger RNA (mRNA and preventing it from making a protein.
The RNAi process is triggered by double-stranded RNA, where one strand is identical to the target mRNA sequence. ddRNAi technology involves inserting a DNA construct into a cell to produce the double-stranded RNA, resulting in the destruction of the target mRNA and silencing the expression of the target gene.
Benitec claims the ddRNAi approach has several advantages when compared with alternative gene silencing technologies under development, such as antisense RNA and siRNA. These advantages include lower cost and ease of preparation, more versatile delivery options, the ability to silence genes in whole organisms (transgenic ddRNAi) and the ability to control the expression and timing of gene silencing.
However, the company has been forced to defend its patent position in ddRNA, with lawsuits
