What’s the Problem with DNA-directed RNAi?

I apologise for having been somewhat quiet recently on the blog. It is not that I lost my belief in RNAi Therapeutics, quite the opposite actually. RNAi has already been shown in hundreds of research labs to be a gift of biology (or God, as one famous biologist, whom I shall leave here anonymous, once noted), and it is now up to many of us individuals and organisations to carefully uncover its therapeutic potential.

One area where progress has been slow is DNA-directed RNAi (ddRNAi). Except for Nucleonics’ Hepatitis B Virus RNAi program, all other clinical studies currently make use of synthetic small interfering RNAs (siRNAs) for therapeutic gene knockdown. While I agree that siRNAs have many advantages over ddRNAi for many applications applications, ddRNAi may be in principle superior to siRNAs e.g. where durable gene knockdown is desirable or where viral delivery methods may get to more efficiently than formulated siRNAs. One can agree that it is an interesting concept to immunise the immune system against HIV by giving the patient stem cells that generate T-cells expressing shRNAs directed against HIV (actually such a trial is imminent at the City of Hope). Why has progress been so slow? ddRNAi-based companies have had great difficulties in attracting funding. Benitec, arguably one of the early contenders to be the darling of ddRNAi, eventually ran out of money, had to cut down most of their development programs and went back to Australia to wait for something good to happen. Instead of focusing on research and investor relations, money was spent on lawyers in early patent battles about rights to ddRNAi. It is interesting that while patent issues are being talked about in the siRNA space, full-blown legal battles about the core siRNA patents have been the exception. It is expected that these will be sorted out at later stages through cross-licensing and royalty agreements, closer to the approval of the first siRNA-based drugs. Makes sense. Another problem is that ddRNAi carries the stigma of being a traditional gene therapy with all the historical ballast of immunogenicity and cancer through insertional mutagenesis.

So how could ddRNAi stage a comeback? One way might be to consolidate the IP in one company and remodel it as a champion of ddRNAi, similar to what Alnylam is for siRNA Therapeutics. This would make investors feel confident that their company has the freedom to operate and attract funding and clinical support through collaborations. This also requires credible management that has access to key decision makers in big biopharmaceutical companies. Failure to do so would not only put the technology at risk of ever being fully developed, but also rob patients of important treatment options.