Celon Pharma Research

RNA interference is a natural process of gene silencing. This pathway is involved in defense against viruses, transposons expansion and post-transcriptional regulation. RNAi is an evolutionarily conserved biological phenomenon in plants and animals.

In a cell long dsRNAs are recognized by Dicer - a member of the RNase III family of dsRNA-specific endonucleases. Cleavage of long dsRNAs by Dicer creates short dsRNAs that are characterized by 2-nt-long 3' overhangs. These are called small interfering RNA (siRNA) and are 21-nt-long in sequence. Than siRNA are incorporated in protein complex called RNA induced silencing complex (RISC). After incorporation of the siRNA RISC unwind it and single stranded siRNA that stays at RISC mediate binding to target mRNA in a sequence-specific manner. Than mRNA is cleaved by RISC. The site of the cleavage falls in the middle of the region of siRNA complementarity. The cleaved mRNA is recognized as being aberrant and destroyed by nucleases.

In contrast to other classes of therapeutics such as proteins, antibodies and small molecules, RNAi requires neither "drugable" domains on the molecular target (e.g. kinase domains) nor specific locations at the cell membrane or extra-cellular.

Furthermore, siRNAs constitutes a well defined chemical entity. Even different siRNAs molecules (sequences) against the same or a different target gene will have similar ADME and toxicology /safety profiles in animals and humans. This implies that once the first siRNAs molecules have been approved for marketing by the regulatory authorities, the development and regulatory process for subsequent siRNAs molecules will be facilitated and more cost efficient. This is not the case for small molecules or antibodies, where each new chemical entity (NCE) commonly has a different composition and synthesis protocol.

The lead identification and optimization of siRNA molecules takes in our labs less than 3 months (vs. up to several years for the same process or e.g. small molecules). The significant reduction of the preclinical development time will lead to a faster way to the clinic.

Because of these advantages Science magazine has elected both the RNAi molecules and the RNAi mechanism as Molecule of the Year in 2001 and as Scientific Discovery of the Year in 2002, respectively. Discoveries of RNAi were awarded Nobel prize2006 in medicine and physiology.

Challenges of RNAi as a therapeutic:

delivery problem

to improve cellular uptake

stability problem

to improve serum stability

"off-target" effect problem

to avoid unspecific silencing

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