Are antagomirs the best compounds that could be practical for treating multiple human diseases? Could companies like Alnylam (ALNY) initiate first clinical trials using antagomirs relatively soon? I believe the answers to both questions are yes.

The paper published a couple of days ago by the scientists from Alnylam, the Rockefeller, and NY University (see the abstract below) provides perhaps the most convincing evidence from animal studies that RNAi-related approaches could be practical for treating multiple human diseases. While the experiments were done in mice, there is little doubt that the approach could be tailored to humans. Two points in the paper are critical. First, there is very specific and potent inhibition of the targeted miRNAs. Second, the application of the drug, antagomir, delivered via simple intravenous injection, affected most tissues in the animals. Both the amounts of antagomirs introduced and the delivery method (intravenous injection) are likely feasible for humans.

When could the first clinical trials be initiated in humans? Now that there is an antagomir tool to knock down miRNAs, what we need are target miRNAs that could be involved in human diseases. While there are many protein coding genes known or suspected to be involved in various diseases, almost nothing is known about miRNAs in this respect. But, this is going to change were quickly via research in the academia and the industry. There are already examples of miRNAs implicated in cancer. For instance, miRNA let-7 is a suspected tumor suppressor. Knocking out a tumor suppressor wont stop cancer. So other miRNAs that are required for cancer survival and not cancer suppression are needed. I am sure the research to locate such miRNAs is in high gear already. We will probably see the first clinical trials using antigomirs in the 1-2 years.

Simple calculation shows that the antagomir dose used on mice (80 mg/kg) translates to about 6 g/injection for an adult person. Now, with 6 g/dose what could be the price tag to synthesize compounds like antagomirs? Antagomir synthesis is essentially the same as synthesis of modified RNA oligonucleotides. My estimates are that antagomirs could cost around 1000$/g or 6,000$/dose for humans. So, even if the drugs effect could last around a month like in mice, the medicine is still pricey. Of course, the price should come down as the scale of the synthesis is increased but I still see the expensive price of synthesis as a potential problem for commercialization of antagomir-base therapies.

Reference:
Nature. 2005 Oct 30; [Epub ahead of print]
Silencing of microRNAs in vivo with 'antagomirs'.
Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M,
Stoffel M.