The Business of RNAi Therapeutics in 2012

Nanoscale Small Interfering RNA Delivery Systems For Personalized Cancer Therapy

“…RNA interference (RNAi) has emerged as an attractive technology for silencing the expression of specific genes in human cells (1)(2)(3)(4)(5)(6). In the physiological RNA interference pathway of gene silencing, double stranded RNAs are processed into small interfering RNAs (siRNA) by the RNase enzyme DICER.…”

“…In the physiological RNA interference pathway of gene silencing, double stranded RNAs are processed into small interfering RNAs (siRNA) by the RNase enzyme DICER. These siRNAs are incorporated into an RNA-induced silencing complex (RISC), that is capable of identifying and degrading mRNA that is complementary to the antisense strand of the siRNA thereby causing "gene silencing" [1][2][3][4][5][6]. However, sequence-specific gene knockdown via RNAi can also be triggered by a variety of synthetic double-stranded siRNA species that are capable of serving as DICER substrates and are therefore being developed as potential RNAi therapeutics candidates [1][2][3][4][5][6].…”

“…These siRNAs are incorporated into an RNA-induced silencing complex (RISC), that is capable of identifying and degrading mRNA that is complementary to the antisense strand of the siRNA thereby causing "gene silencing" [1][2][3][4][5][6]. However, sequence-specific gene knockdown via RNAi can also be triggered by a variety of synthetic double-stranded siRNA species that are capable of serving as DICER substrates and are therefore being developed as potential RNAi therapeutics candidates [1][2][3][4][5][6]. Several formidable obstacles exist for the development of siRNA as RNAi therapeutics, including their rapid degradation by nucleases in the blood, poor cellular uptake, and requirements for endosomal escape after cellular uptake, off-target effects due to their microRNA-like activity profile, and their inflammatory effects [7][8][9].…”

“…The siRNA delivery systems that have emerged during the last decade revolve around liposomal formulations [1][2][3][4][5][6][7][8][9][10], non-bilayer self-assembled polymeric nanoparticles [9], [11][12][13][14][15], and to a lesser extent, tertiary hybrid systems where lipids, polymers or solid cores are utilized [16][17][18]. The pharmacological effectiveness of oligonucleotidebased therapeutics depends on their cellular uptake, intracelular trafficking, endosomal release, and productive delivery to their target subcellular compartments [19,20].…”

“…In nearly all of the contemporary siRNA systemic delivery systems in development, the use of siRNA complexation has become almost a universal procedure for packaging siRNA into either lipid-based or polymer-based nanoparticles. siRNA cargo is complexed and compressed, meaning that its polyanionic charges are neutralized and its size made smaller [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Compression of the siRNA cargo takes place when it forms a complex with cationic materials including cationic lipids (lipoplex) and polycationic polymers (polyplex).…”