miR-122 is a talented regulator. Sure it can negatively regulate gene expression by binding 3’ UTRs of target mRNAs, but it’s also shown that it can bind 5’ UTRs in the HCV genome just as well, and act as a positive regulator, giving the virus a hand with replicating its genome. Facilitating viral replication? Well, nobody’s perfect.
Because it’s essential for HCV replication, miR-122 has been on the hit list of several groups keen on developing HCV antiviral therapies. Well the holidays came early for a team of researchers from the Southwest Foundation for Biomedical Research (SFBR), Santaris Pharma, and the Copenhagen Institute of Technology (CIT) who published work illustrating a promising approach that puts a cellular smackdown on miR-122 compliments of a locked nucleic acid (LNA) modified oligo.
Unlike current therapies that only help about half of those treated and cause life-threatening side-effects, the LNA treatment resulted in a long-lasting reduction of HCV genome levels in three out of four chimps tested, and the only side-effect was low cholesterol. Not bad.
LNA on the Rise
Researchers at Santaris have been working on harnessing the promising LNA technology as an alternative to regular oligos for down-regulating miRNAs for years now. Although LNA has been around for quite some time now, miRNA manipulation has provided an application that is perfectly suited to LNA’s higher binding affinity and enhanced stability relative to other oligos, both key traits for in vivo applications.
The folks at Santaris had previously bench tested LNA inhibitor (SPC3649) in non-human primates for (Elmen et al., Nature 2008) and decided it was time to step it up into HCV in chimps. Why chimps? Well, chimps are the only animals, except for humans, that get HCV. Also, “as the first miRNA inhibitor in clinical trials, we recognize that SPC3649 is breaking new ground, so we wanted to conduct the chimpanzee study to be maximally sure that the drug was safe and provided clinical benefits” before going into humans, says Henrik Ørum of Santaris.
In this proof-of-concept study, baseline measurements were taken on four chimps. Then, two chimps received a high dose of the LNA, and two got a low dose. HCV genome levels declined significantly in the serum of three of the four chimps. In liver biopsies, miR-122:SPC3649 heteroduplexes were observed in high-dose animals, which shows that the LNA was working as expected. The treatment reduced the expression of interferon-responsive genes (IRGs), so it might help patients who have high IRG expression and do not respond to the conventional interferon therapy. In contrast to a previous report suggesting that LNAs cause hepatotoxicity, the treatment appeared to be completely safe.
Resistance is Futile
An important finding was that the chimps did not develop resistance to the therapy. HCV RNA levels stayed low for months after treatment because the LNA was so stable. Also, the virus didn’t try to get around the LNA by mutating its own miR-122 seed sites. Robert Lanford of SFBR attributes this mostly to the fact that SPC3649 binds a host factor, unlike most other new drugs, which target viral factors. “We’re targeting a liver-specific factor that the virus requires for replication,” he notes. “It had never been done in animals, so we weren’t sure how well it was going to work. It turned out to work exceptionally well.”
So well, in fact, that Santaris has taken SPC3649 through two dosing studies on healthy humans and will start the first clinical trial with the drug in patients early next year. Lanford says he is excited that SPC3649 could be used as a replacement for interferon or in combination with interferon or other antivirals. “So, it’s a pretty exciting event,” he notes. “The other excitement really is that it indicates that locked nucleic acids really have a good potential as a therapy for other diseases.”
To find out more about this ground-breaking study, check out Science, January 2010 later today for the details.
To learn more about LNA and how it can help you out in other miRNA analysis applications, check out Exiqon’s site.