RNA Interference Approach

Bcl-2 B cell lymphoma protein 2 (Bcl-2) is a family of proteins that regulate apoptosis (programmed cell death). Apoptosis is a necessary process whereby aged or damaged cells are replaced by new cells. Dysfunction of the apoptosis process results in disease inhibition of apoptosis results in cancer, autoimmune disorder, and viral infection, whereas increased apoptosis gives rise to neurodegenerative disorders, myelodysplastic syndromes, ischemic injury, and toxin-induced liver disease. 

Some lymphomas, for example, are related to overexpression of Bcl-2. Antisense oligonucleotides are specially designed to target the overexpression of Bcl-2. Oblimersen (Genasense) is an antisense drug by Genta to block Bcl-2 production and enhance the efficacy of other standard chemotherapy drugs such as paclitaxel, fludarabine, irinotecan, and cyclophosphamide. 

ICAM-1 Intracellular adhesion molecule 1 (ICAM-1), an immunoglobulin, plays an important role in the transport and activation of leukocytes. In Crohn s disease (inflammation of the alimentary tract), there is an overexpression of ICAM-1, which causes inflammation. Laboratory studies show that antisense oligonucleotides can reduce the expression of ICAM-1 and hence inflammation. 

Source Opalinska JB, Gewirtz AM. Nucleic-acid therapeutics basic principles and recent applications, Nature Reviews Drug Discovery 1 503-514 (2002). 

Currently, there is only one antisense drug on the market— Vitravene (active ingredient fomivirsen) for the treatment of cytomegalovirus (CMV)-induced retinitis (inflammation of the retina) in AIDS patients. Fomivirsen has 21 nucleotides complementary to a CMV mRNA sequence, which is necessary for the production of infectious virus. Two examples of experimental antisense drugs are provided in Exhibit 3.15, while Table 3.1 lists other antisense drugs in clinical phase. 

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Other approaches directed to the mRNA of tyrosine kinase and thereby interfering with their translation to proteins, such as anti-sense therapy and RNA interference (RNAi) are less advanced and currently limited to laboratory studies. 

Berkhout B (2004) RNA interference as an antiviral approach targeting HlV-1. Curr Opin Mol Ther 6 141-145... 

There are two main approaches to discovering small molecule drugs the irrational approach or the more recent structured rational approach. Antisense, RNA interference, and chiral drugs are other drug discovery methodologies. 

GrunweUer, A., Hartmann, R.K. (2005) RNA interference as a gene-specific approach for molecular medicine. Curr. Med. Chem., 12, 3143-3161. 

Dykxhoorn DM, Chowdhury D, Lieberman J (2008) RNA interference and cancer endogenous pathways and therapeutic approaches. Adv Exp Med Biol 615 299-329... 

Robinson, K.A. and Beverley, S.M. (2003) Improvements in transfection efficiency and tests of RNA interference (RNAi) approaches in the protozoan parasite Leishmania. Molecular and Biochemical Parasitology 128, 21 7-228. 

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