Overcoming Negative Perceptions
Despite some of the current negativity around RNAi therapeutics, the fact remains that more than 1,000 patients and volunteers have been recipients of RNAi drug candidates with acceptable and improving safety profiles. A number of trials have involved doses where robust target gene knockdown can be expected based on rodent and nonhuman primate preclinical studies.
Important knockdown efficacy results are expected in the next two to five months from Alnylam’s ALN-TTR01 and ALN-PCS Phase I studies in TTR amyloidosis and hypercholesterolemia. Together with the safety data from studies involving RNAi candidates for cancer therapy—Alnylam’s ALN-VSP02, Silence Therapeutics’ Atu027, and Tekmira’s TKM-PLK1—these results have the potential to boost confidence in RNAi therapeutics.
Progress in the commercialization of transgenic RNAi plants and animals is more advanced due to the decreased importance or absence of innate immunostimulatory issues, lowered safety bars, and, in the case of plant RNAi, often highly potent gene-silencing outcomes.
As much as establishing stable transgenic RNAi lines and achieving potent DNA-directed RNAi in all mammalian tissue types of interest continues to present technical challenges, it is the cultural resistance to gene-modified organisms in many parts of the world that may be rate-limiting in adopting RNAi for improving human nutrition and creating cleaner environments.
With RNAi plants (including blue rose, which may soon reach the marketplace), one can expect further commercialization of RNAi crops. This will be the case especially for pathogen and environmental resistance and, following that, for the improvement of nutritional values.
RNAi techniques leading to an increase in the yield and quality of therapeutic recombinant proteins produced via plant and animal cell culture systems are also poised to become commercialized technologies over the next decade or two.
On the biomedical front, RNAi has become a critical research tool. Ubiquitously used in target discovery and validation, it is already having a great impact by increasing the efficiency of drug development. Experience with the technology and the improved affordability of RNAi reagents and transcriptomic analysis tools suggest that the quality of the results obtained from RNAi experiments should increase steadily.
In the therapeutics space, arguably the area of highest commercial potential for RNAi, one can expect continued improvements in the safety and efficacy of existing RNAi delivery platforms. Nonhuman primate data indicates that RNAi is already 100- to 1,000-fold more efficient in inducing gene silencing in the liver compared to the older RNaseH antisense technology (single-digit microgram/kg versus single-digit milligram/kg ED50s).
Moreover, one can expect the development of new delivery technologies for gene knockdown beyond applications for the liver, solid cancers, and endothelial cells. Such candidates include dermal, respiratory, and hematopoietic cells.
Efforts in targeting the related microRNA pathway for therapeutic purposes also have made steady progress and look particularly promising for oncology indications and the treatment of hepatitis C infection. In addition, interesting applications in areas such as cardiovascular disease are emerging.
Taken together, given the maturing state of RNAi technologies and their stage of clinical development, the first regulatory approvals of small silencing RNAi therapeutics should occur in five to seven years.