siRNA therapy side effects

[radin]

Dear friends,

I like to disscuss about siRNA side effects, everyone that know about this can participate in this disscuss.

For example in a orginal article, in clinical trials of the siRNA they considered that siRNA interacts with some receptors on ocular systems and has some side effects on it.

but we can solve this problem by coating the siRNA, like encapsulate them with PEI-PEG system.

What's your opinion?

[Jon Moulton]

An encapsulation scheme that prevents interaction of the siRNA with cell-surface receptors could eliminate some side effects. However, the off-target modulation of gene expression characteristic of small dsRNA will still occur.

Here are some citations addressing this off-target gene modulation.

Comparison of siRNA-induced off-target RNA and protein effects. Aleman LM, Doench J, Sharp PA. RNA. 2007 Jan 19; [Epub ahead of print]

Retraction of synapses and dendritic spines induced by off-target effects of RNA interference. Alvarez VA, Ridenour DA, Sabatini BL. J Neurosci. 2006 Jul 26;26(30):7820-5.

3' UTR seed matches, but not overall identity, are associated with RNAi off-targets. Birmingham A, Anderson EM, Reynolds A, Ilsley-Tyree D, Leake D, Fedorov Y, Baskerville S, Maksimova E, Robinson K, Karpilow J, Marshall WS, Khvorova A. Nat Methods. 2006 Mar;3(3):199-204.

Nonspecific, concentration-dependant stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). Persengiev SP, Zhu X and Green M. RNA 2004; 10:12-18.

Transcriptional gene silencing by short interfering RNAs. Kawasaki H, Taira K. Curr Opin Molec Therap. 2005 7(2):125-31.

Small interfering RNA-induced transcriptional gene silencing in human cells. Morris KV, Chan SWL, Jacobson SE, Looney DJ. Science 305(5688):1289-92.

A rapid and sensitive assay for quantification of siRNA efficiency and specificity. Smart N, Scambler PJ, Riley PR. Biol Proced Online. 2005;7:1-7. Epub 2005 Jan 24.

Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Scacheri PC, Rozenblatt-Rosen O, Caplen NJ, Wolfsberg TG, Umayam L, Lee JC, Hughes CM, Shanmugam KS, Bhattacharjee A, Meyerson M, Collins FS. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1892-7. Epub 2004 Feb 09.

Expression profiling reveals off-target gene regulation by RNAi. Jackson AL, Bartz SR, Schelter J, Kobayashi SV, Burchard J, Mao M, Li B, Cavet G, Linsley PS. Nat Biotechnol. 2003 Jun;21(6):635-637.

Small RNAs with Imperfect Match to Endogenous mRNA Repress Translation: Implications for off-target activity of small inhibitory RNA in mammalian cells. Saxena S, Jonsson ZO, Dutta A. J Biol Chem. 2003 Nov 7;278(45):44312-44319.