siRNA delivery difficulties to meet a sticky end?

RNA interference offers a way of blocking protein production without the problems of strand invasion and triple helix formation common to gene silencing. However, to date developers have encountered considerable difficulties when attempting to deliver siRNA sequences. For example, while non-viral delivery vectors such as cationic lipids are free of the immunogenic properties of their viral counterparts, they only loosely bind siRNA sequences. As a result, the RNA molecules often disassociate from the vector in the presence of polymeric anions on surface of target cells, preventing their entry into the cytoplasm. Nevertheless, in the last few years an increasing number of pharmaceutical majors have begun employing siRNA techniques in drug design, screening and validation. In 2007 for example, Switzerland's Roche paid Alnylam Pharma $1bn for rights to its siRNA technology, while AstraZenca and Merck & Co have also established similar deals with RNAi specialists. Effective delivery is major stumbling block ​​At present, the delivery of genetic material for therapeutic purposes is achieved using either viral vectors or non-viral carrier molecules. Products that utilize adenoviral vectors, including Introgen Therapeutics' ADVEXIN p53 and INGN 241 mda-7, as well as those developed by UK-based Eden Biodesign, currently dominate the market. However, such vectors are expensive to grow, difficult to store and are potentially immunogenic. In addition, adenoviral vectors are more suited to delivering the double stranded molecules used in gene therapy than single stranded RNAi molecules, as the former more closely resemble the genetic material contained in wild-type virus. Subsequently, alternative delivery carriers based on cationic lipids and polymers have been developed that are cheaper to make and can be stored for extended periods are being developed. SsiRNA more stable ​ As their name suggests, ssiRNAs stick together due to short complementary runs of adenosine and thymine bases that have been added to the end of each molecule. These larger, more stable structures are tightly bound by cationic delivery vectors and, as a result, can pass more easily through the target cell wall into the cytoplasm and begin mediating their therapeutic effects. Polyplus commented that the ssiRNA technology, in combination with its recently launched cationic polymer delivery vector in vivo jetPEI, has the potential to improve delivery efficiency and avoid some of the potential limiting toxicities that are associated with lipid-based vectors. Jeanne-Françoise Williamson, Polyplus' technical support manager told in-PharmaTechnologist.com that the firm will target the in vivo​ RNAi development market through deals with industrial oligonucleotide manufacturers and pharmaceutical firms. ​​​