It takes precision, focus and persistence to perfect the art of origami. So perhaps it is no accident that researchers have needed to apply the same skills to overcome challenges in siRNA delivery, right down to the folding.
A couple of years ago, my fellow blogger Paul Krzyzanowski introduced us to RNA interference (RNAi) technology. RNAi is a process that occurs within cells to silence gene activity by destroying messenger RNA (mRNA) molecules and subsequently preventing the production of a specific protein. (Reminder: DNA sequence is transcribed into mRNA and mRNA instructs the production of proteins.)
RNAi has generated excitement for potential therapeutic applications as RNAi could target mRNA molecules that lead to mutant or excessive protein production in disease. Pharmaceutical companies took notice and a number of experimental therapies have entered clinical trials to treat diseases such as macular degeneration, hepatitis B and liver cancer.
In the case of liver cancer, Alnylam Pharmaceuticals has generated an RNAi strategy targeting two genes: a cancer proliferation gene and a gene involved in blood vessel development to arrest tumour growth (blood vessels feed tumours). So far, Phase I clinical trial results are promising.
RNAi pharmaceuticals hold major advantages in ease of design, relatively fast production and highly specific targeting. While these are sizable advantages in pharmaceuticals, a number of unforeseen challenges have arisen.
The greatest challenge for RNAi pharmaceuticals is the efficacious delivery of siRNA to affected cells within the body. siRNAs contain negative charges, so they do not easily enter a cell through its hydrophobic membrane, which has limited clinical applications. This siRNA delivery problem has been very difficult to solve. So far, siRNA delivery methods have included viruses, nanoparticles, liposomes and immunoconjugates (antibodies coupled to toxic agents), all of which have created their own set of challenges.
As a result of these delivery problems, pharmaceutical companies, including Pfizer and Roche, withdrew from the siRNA therapeutic space. However, despite declining interest from Big Pharma, many researchers are working feverishly to improve siRNA delivery methods. Researchers continue to optimize lipid nanoparticles as delivery vehicles, particularly for systemic delivery of siRNA to healthy, as well as cancerous, livers. They have been used in clinical trials.
Last month, chemical engineers at MIT published a novel siRNA delivery strategy based on a different type of nanoparticle. The article published in Nature Nanotechnology describes a siRNA delivery system that uses a technique called “nucleic acid origami.”
In the nucleic acid origami technique, short nucleic acid polymers are programmed to self-assemble into folded two- and three-dimensional shapes at the nanoscale level. In this study, siRNA molecules were linked to DNA molecules before assembly and upon folding they were incorporated into the three-dimensional shapes. Folate molecules (vitamin B9) were also affixed to the DNA structures to target the large number of folate receptors found on certain tumours. These custom DNA structures successfully increased cellular uptake of siRNAs.
A major advantage of these three-dimensional DNA structures is their ability to produce large quantities of identical shapes, allowing greater control and sensitivity of delivery.
The ability to design custom DNA structures and shapes is the reason that these nanostructures have been dubbed “designer DNA.” Designer DNA is stirring up excitement in the RNAi field and even if they don’t contribute to RNAi therapeutics, they will definitely be a cool tool for understanding small RNA biology.
Angela C. H. McDonald
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