Antibody-Protamine Complexed siRNA View image detail

The liver is a natural first frontier for exploration of systemic delivery approaches due to its natural role in maintaining blood homeostasis, which means that most drugs will pass through and enter this organ. Most progress in systemic delivery has been achieved in targeting siRNAs to the liver following intravenous administration of a number of different formulations. In many cases, potent gene silencing has been observed, including demonstration of potent silencing via RNAi in non-human primates. The first clinical trials using these formulations are now beginning for a number of liver-associated conditions such as primary and metastatic liver cancers and hypercholesterolemia.

For other tissues, however, active targeting strategies and improved pharmacological attributes are likely required. As it will logically take the siRNA longer to accumulate in tissues that are deep inside the body, the risk for premature enzymatic degradation of the siRNA increases when these tissues are the drug target. Stability of the siRNA within the therapeutic composition is therefore an important consideration in the design of systemic RNAi therapeutics. For example, just packaging the siRNA into nanoparticles will not only enhance cellular uptake, but also significantly stabilize the siRNA. Additionally, siRNA modification with medicinal chemistries, many of which have already been used in FDA-approved drugs, can further increase their stability without negatively affecting their gene silencing activity. Importantly, once the siRNA has reached the cytoplasm of the cell, it is typically active for a period of weeks.

Targeting siRNAs by exploiting tissue-specific features is another major area of research yielding promising systemic siRNA delivery solutions. One example is linking siRNAs to antibodies that recognize tissue-specific cell surface proteins. An additional example is RNA itself in the form of so called RNA aptamers. Aptamers are RNAs that assume 3-dimensional structures that when appropriately selected will allow them to bind to defined structures with high specificity and affinity.