As a synthetic organich chemist, I have worked in the field of antisense drugs (in the form of contract research) for US companies (ISIS, Geron etc) and am really excited to see the evolution of generation 2.5 antisense drugs.
Antisense therapy is a form of treatment for genetic disorders or infections. When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively turning that gene “off”. This is because mRNA has to be single stranded for it to be translated. Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA. This synthesized nucleic acid is termed an “anti-sense” oligonucleotide because its base sequence is complementary to the gene’s messenger RNA (mRNA), which is called the “sense” sequence.
We know that, specificity and simplicity are two major advantages of the antisense approach for discovering novel inhibitors of protein expression. Antisense oligonucleotides act by targeting virtually any region (including non-translated sequences) within a pre-mRNA or mRNA, as a result of the degeneracy of the genetic code it is relatively straightforward to identify an antisense oligonucleotide that inhibits a member of a multigene family in a highly specific manner.
Diverse pipeline of drugs: Antisense drugs are being researched to treat cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, ALS, Duchenne muscular dystrophy and diseases such as asthma and arthritis with an inflammatory component. Most potential therapies have not yet produced significant clinical results, though one antisense drug, fomivirsen (marketed as Vitravene), has been approved by the US-FDA as a treatment for cytomegalovirus retinitis. ISIS is expecting the clinical study (2010) to support the first regulatory filings in the U.S. and E.U. for Mipomersen.
The evolution of the technology (through chemical modification ):
The advancement from the zero generation (phosphodiester) to first generation (entirely DNA-like e.g., phosphorothioate) lead to the advantages like resistant to degradation, increasing stability in the blood stream (and in tissues) and preventing rapid elimination of the drug from the body.
Second-generation drugs are composed of both RNA-like and DNA-like nucleotides (ISIS has many drugs in its pipeline in this category). Here in RNA hybridizes more tightly to RNA than to DNA, the second-generation drugs have a greater affinity for their RNA targets and, therefore, greater potency. As per the claim by the researchers, the modifictation (2’MOE) slows degradation of the drugs by protecting them from nucleases and also offers the potential for more convenient oral delivery.
Researchers from ISIS claim that, there are at least 12 known antisense mechanisms that can be exploited once an antisense drug binds to its target RNA. They have created proprietary chemical modifications to trigger many of these mechanisms for drug discovery. Out of 12, three mechanisms are being widely studied, they are RNase H mechanism (main focus of ISIS), RNAi (siRNA – si-small interfering, to target an mRNA sequence) and Alternative Splicing (e.g., ISIS-SMNRx , for spinal muscular atrophy, SMA).
ISIS and Alnylam have jointly established ‘Regulus‘ as a company focused on the discovery, development and commercialization of microRNA-based therapeutics (out of 700 microRNAs in the human genome are believed to regulate the expression of approximately one-third of all human genes).
We should appreciate the courage and confidence (despite major disappointment in 2003 and FDA’s rejection of Genasense) of ISIS and other companies. ISIS’s CEO Stanley Crooke appears confident that the technology has progressed enough and its “generation 2.5” antisense chemistry will lead to improved molecules (10 times more potent than its current drugs) with oral dosing a viable proposition. Let us be optimistic, because modern medicinal chemistry still need luck to a certain extent and luck doesn’t favor the computer, but prepared (open) mind…..
Stay tuned! …..