Antisense oligonucleotides: the promise and the problems

Published on December 31, 2015   45 min
0:00
Welcome, everyone. My name is Dr. Kendall S. Frazier. I'm a Director of Pathology at GlaxoSmithKline in King of Prussia, Pennsylvania in the United States. Today, I'd like to talk about a new and expanding field of drug development that involves antisense oligonucleotides. I'll talk about their promise and their problems.
0:21
So antisense oligonucleotide therapies have been around since approximately 1993. The first generation phosphorothioate oligoantinucleotides were much less stable and had poor efficacy as compared to the products that we have now. The original ASO molecules, ASO meaning antisense oligonucleotides, did not effectively enter cellular compartments. They had poor solubility and rapid degradation by exonucleases, which led to the development and clinical introduction of the so called second generation ASOs, where they were substitutions of the phosphate backbone. If you look at this slide to the right, you see at the two prime position methoxyethyl or also O-methyl substitutions were created which made more stable molecules. They had very predictable toxicity, but they also had proinflammatory effects. From 2002 to the present, we were using primarily the second generation oligonucleotides as therapies. However, in about 2005, the third generation oligonucleotides were developed. These included the locked nucleic acids and the short interfering RNAs and aptamers. Short interfering RNAs or the siRNAs are really not true antisense oligonucleotides, they use a separate form of inhibition of RNA. However, they've become more widely available and are actually more efficacious. The LNA's are in use by many companies at present but we still have a large number of phosphorothioate second generation or generation 2.5 oligonucleotides active in clinical trials. In 2011 we started seeing a new generation, some people call these third generation plus or fourth generation antisense oligonucleotides. They include constrained ethyl phosphorothioates and bicyclic nucleic acids with N-methyl substitutions. And finally we have Gal-Nac conjugated oligonucleotides. Those are oligos linked with N-acetylgalactosamine. Using these types of conjugated exogenous ligands, the ASO or siRNA multivalent molecule binds with high affinity to the asialoglycoprotein receptor and these are expressed on liver cells and get rapidly incorporated into the cytoplasm of the hepatocyte. There are also tricyclic DNA oligonucleotides which are just now coming on the scene and have shown some really exciting efficacy.
3:07
So why is there promise for ASO therapies? Well, it's due to several reasons. One of those is that mipomersen, a drug that was developed by two companies out on the west coast, has recently been registered by the FDA in the United States, despite having class-wide toxicity issues. This is a molecule that has been shown to clinically have great efficacy in treating a particular kind of inherited liver disease. We've also got screening strategies across the industry that really have helped eliminate a lot of the problem molecules that we've been dealing with for five or ten years. In other words we can screen out the bad players and end up with a series of molecules that have the best chance for reaching the market and helping disease. Most of the compounds now that have reached phase two or phase three in drug development really have very limited hepatotoxicity or nephrotoxicity. And finally, there is a new understanding of off-target nucleotide binding and these off-target effects that many have worried about for the various classes of antisense oligonucleotides. We've been able to understand that base pair length and binding affinity can mitigate these off-target effects. And we've used those strategies to allow us to pick the best potential candidates for drug development. Very recent advances in the science of new generation antisense oligos have resulted in marked improvements in efficacy and really no apparent increase in toxicity. Such as the Gal Nacs, we have binding of antisense oligos to other molecules or to cellular surface proteins that allow intracellular targeting. We also have other new molecules that have improved profiles, some with really good tissue penetration and less frequent dosing paradigms. And as well there are new delivery systems including exosome or nanoparticles, which allow us to get the antisense oligonucleotide within the cellular compartment. Finally, recent investigative work within the pharmaceutical industry has provided new insight into the mechanisms of many of the class-wide toxicities that we've been dealing with. And this has allowed progression through the regulatory hurdles and really as in mipomersen that I discussed to allow now antisense oligonucleotides to be registered within the United States and within Europe.
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Antisense oligonucleotides: the promise and the problems

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