After listening to the presentations of a number of RNAi Therapeutics companies at the BIO CEO & Investor Conference, I came away thinking that while we are rightfully focused on discussing the challenges of RNAi Therapeutics, underneath of it there is a powerful wave of RNAi delivery solutions building and that is making its way into the clinic.
As a number of the presenters rightfully pointed out, there is not one universal delivery solution, such that this wave consists of various approaches addressing one cell and tissue type after another. Given that a cell/tissue is relevant for many diseases and given that there may be more than one suitable cell/tissue type for most diseases, this means that RNAi Therapeutics is quickly becoming broadly relevant for drug development. It is also true that while 21-23bp siRNAs will be the sweet spot for most applications, different siRNA lengths may work best for different delivery solutions, and which is facilitated by the remarkable robustness of RNAi in our cells that efficiently recognizes many forms of dsRNAs as substrates for RNAi.
To mark the occasion, I have compiled below a list of organs together with what I consider the leading respective delivery technologies. The list does not seek to exclude other technologies that could also be used for a given organ, but which are somewhat behind in development. The list is in order of clinical maturity with green highlighting those that I consider ready for prime-time, orange for those that are just on the verge, and red those that look very promising, but will require more research before I would feel confident about their clinical success.
The orange category is particularly exciting, because RNAi in immune cells looks like a low-hanging fruit waiting to be picked. Particularly when it comes to phagocytic cells such as dendritic cells that are important for vaccines, the opportunity lies in taking advantage of the natural tendency of siRNA nanoparticles to be taken up by such cells while there is increasing evidence that with the right chemistry you can get functional release of siRNAs into the cytoplasm instead of their degradation in phagosomes. I similarly feel that a renaissance of RNAi for the eye is in order given that DNA vectors and siRNA-conjugates are just begging to be applied as the unmet need grows in the exponentially ageing population.
Liver: cationic liposomes
Solid cancer proper: cationic and targeted liposomes
Endothelial cells: lipoplex/Atuplex
Phagocytic cells: liposomes
Other immune cells (incl. cancer of blood): targeted immunoliposomes
Eye: lipophilic-siRNA conjugates and ddRNAi (AAV and lenti)
Respiratory epithelia (incl. lung): modified siRNAs (inhalation; topical)
Brain (instillation): lipophilic-siRNA conjugates and ddRNAi (AAV and lenti; instillation)
Injured skin: lipophilic-siRNA conjugates (topical)
Heart and intestine: lipophilic-siRNA conjugates in reconstituted lipoproteins (intravenous)
Kidney: modified siRNAs (intravenous)
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