Sirna Therapeutics

Li L, Shen Y (2009) Overcoming obstacles to develop effective and safe siRNA therapeutics. Expert Opin Biol Ther 9 609-619... 

The accessibility of different tissue types, the presence of various delivery routes, and a variety of pharmacological requirements makes it impossible to have a universal in vivo delivery system suitable to every scenario of siRNA delivery, hi terms of in vivo delivery vehicles for siRNA, the nonviral carriers are the major type being investigated so far, though some physical and viral delivery approaches are also very effective. The routes of in vivo deliveries are commonly categorized as local or systemic. Some of the delivery vehicles and dehvery routes are very effective in animals for target validation but may not be useful for delivery of siRNA therapeutics in humans (Fig. 3.3). Therefore, in vivo siRNA delivery carriers and methods can also be classified as clinically viable and nonclinically viable, according to their suitability for the human use. 

The s U modification in the wobble position of tRNA has one of the greatest effects on RNA stability of any single modification. The large stabilization provided by this nucleoside and the strong A-U versus G-U discrimination of s U suggest the potential for application in the area of siRNA therapeutics. Nawrot and coworkers found that in 5-7 s U, modifications in an siRNA duplex raised the from near 80 °C in 15, 17, and 19 bp duplexes to over 95 °C for the modified duplexes. This modification may see increased application in the siRNA field since the modifications are tolerated by the siRNA machinery, and may modulate binding to other cellular sites, such as toll-like receptors. ... 

The second major (and more recent) focus in the literature is on the PK properties of various embodiments of siRNA therapeutics. Excitement has grown recently with our increased understanding of the mechanisms responsible for the endogenous pathways of posttranscriptional gene silencing, also known as RNA inter-... 

Outright acquisition by a big pharma company has always been a third possible endpoint. Investors, of course, would probably react warmly to this, as it means that a premium to the current stock price would be offered for the purchase, allowing many of them to make money on their investment. Record amounts of money are now flowing into such acquisitions, a recent example being Merck s acquisition of the RNAi company Sirna Therapeutics for 1.1 billion, a premium of just over 100%. 

Another assumption that dsRNA with less than 30 nucleotides (read, siRNAs) will never cause an interferon response has also been called into question. These kinds of problems are to be expected for such a young technology, but in many ways the most remarkable thing is how far it s come in such a short time. RNAi therapeutics are already undergoing clinical trials and one of the companies most involved in the technology, Sirna Therapeutics, was recently acquired by Merck for more than 1 billion, which indicates just how promising the industry feels this technology ultimately is. 

In this chapter, we will highlight the RNAi mechanism, utility of RNAi in screening oncogenes, and cancer-associated genes involved in different cellular pathways. We will also discuss the challenges in developing siRNA therapeutics, as well as the targeted delivery of siRNA. 

The major bottleneck in the development of siRNA therapeutics is the efficient delivery of siRNA to target cells. The difficulty is mainly due to the... 

CALAA-01 is the first targeted delivery of siRNA in humans and was used to treat the first patient in a Phase I clinical trial in May 2008. The trial is a safety study treating adults with solid tumors who are refrartory to standard-of-care therapies. CALAA-01 is administered via a 30 min i.v. infusion on days 1, 3, 8, and 10 of a 21-day cycle. The treatment of patients with CALAA-01 ushers in a new era of targeted experimental therapeutics. Other formulated siRNA therapeutics are sure to foDow CALAA-01, and it will be interesting to monitor the progress of these experimental treatments in the upcoming years. 

This chapter broadly describes the lead optimization activities relevant to the development of novel conjugate siRNA therapeutics for hepatic targets via subcutaneous administration. For specific information regarding other therapeutic oligonucleotide technologies (e.g., antisense, aptamer, CpG, anti-miR), specific nanoparticle-based delivery systems, or non-hepatic targeting, readers are directed elsewhere (Bennett and Swayze, 2010 Kole et al., 2012). 

Because siRNA therapeutics act through a common mechanism of action, robust screening pipelines for a broad variety of targets and indications can be established with a minimum... 

Wittrup, A., Lieberman, J. (2015). Knocking down disease a progress report on siRNA therapeutics. Nat Rev Genet, 16, 543-551. 

Lorenzer, C., Dirin, M., Winkler, A.M., Baumaim, V., Winkler, J., 2015. Going beyond the liver progress and challenges of targeted delivery of siRNA therapeutics. J. Control. Release 203,1-15. 

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