RNAi-based therapeutics: Delivery is key and relevant to insects

Dimitrios Kontogiannatos, Ph.D., Postdoctoral Researcher, Biotechnology Department, Agricultural University of Athens More About the Author

Specific gene knockdown after exogenous small interfering RNA (siRNA) injection into humans and mammals holds great promise for therapeutic applications. But enthusiasm  waned and some predict its demise because of the manifold problems in delivering the technology.

A new review paper in Trends in Biotechnology entitled: “Are RNAi and miRNA therapeutics truly dead?” claims that the new breakthrough technologies in nanomedicine may now help the vast potential of RNAi therapeutics to be fulfilled.

This is of potential interest to insect biologists because the great potential of RNAi-based gene silencing in insects remains unfulfilled for many of the same reasons.

Simplified view of RNAi therapeutics.

RNA interference, an endogenous RNA-based mechanism of eukaryotic cells by which selected gene silencing or shift in gene expression is triggered by sequence-specific double stranded RNAs (dsRNAs), has attracted great interest for its enormous potential in several commercial applications including Medicine and Green Biotechnology.

In therapeutic applications dsRNA molecules pass through several biochemical and mechanical obstacles until they will reach the infected cells. After dsRNAs reach the target cell are being prohibited to cross its membrane due to their high hydrophilicity and large size; consequently an efficient transportation system is needed in order the dsRNA will penetrate the cell.

In addition, the difficulty of delivering siRNAs selectively to diseased cells resulted in limited enthusiasm from pharmaceutical companies for investing in RNAi therapeutics, even if several pioneers like Merck, Roche, Pfizer, Novartis, Alnylam Pharmaceuticals and Takeda had focused in the past in acquiring siRNA therapeutic technologies.

Unfortunately, forward momentum reversed since the technological and technical restrictions of RNAi (e.g. delivery system techniques) did not actually meet the expectations of most companies.

But are RNAi-based therapeutics really dead?

Efficient nanovehicles for siRNA and miRNA delivery are now changing the whole philosophy of RNAi technology leading to a total reassessment of RNAi therapeutics; the global RNAi drug delivery market using nanomaterials is expected to grow to nearly $24 billion by 2015 at a 5 year compound annual growth rate of 27.9%!

Therapeutic RNAi

The mechanism and delivery strategies for RNA interference. – See more at: http://www.mdpi.com/1424-8247/6/1/85/htm#sthash.6qo5xYSs.dpuf

The RNAi industry is ‘back in business’.

Several companies have brought RNAi back to the front page with strong long-term investments. Successful products such as siRNA lipid-based nano-particles (ALN–VSP02) that target KSP and VEGF for the treatment of solid tumors, or ALN–PCS02, which targets PCSK9 for hypercholesterolemia therapy, have showed success in clinical trials and are ready to reach the market. Mipomersen an antisense therapeutic that targets the mRNA for apolipoprotein B, became a success story as a cholesterol-reducing drug candidate. The locked nucleicacid (LNA)-based drug candidate Miravirsen, developed by Santaris Pharma, has also become a huge success as a potent and selective inhibitor of miR-122, a liver-specific microRNA that hepatitis C virus requires for replication.

Mipomersen, an antisense therapeutic

Systemic RNAi delivery should now be replaced with smart delivery systems that enable local targeted and selective uptake and increase their stability and residence time at the site of interest.

These new technologies hold great promises for further evolution of RNAi therapeutics leading in a new era for Medicine, Pest management, Green Biotechnology, Molecular Biology, Functional genomics including Insect Functional Genomics.


João Conde and Natalie Artzi. 2014. Are RNAi and miRNA therapeutics truly dead? Trends in Biotechnology. Article in press   doi:10.1016/j.tibtech.2014.12.005

More About the Author


Post a Comment

Your email address will not be published. Required fields are marked *