Sunday, December 6, 2009

Anti-miR122 Antagomir Successful in Fighting HCV in Chimpanzees

I just wanted to post this video by KENS 5 on the anti-miR122 studies in HCV-infected chimpanzees by Danish LNA company Santaris and researchers from the San Antonio Southwest Foundation for Biomedical Research. The study, just published online in Science, shows surprisingly potent reduction of HCV levels (2 1/2 logs) with an miR-122 antisense inhibitor and, at least equally important, without the emergence of viral escape mutants. While this study only involved four chimpanzees and human studies are still in the early phases (phase I, healthy volunteers), these results justify hopes that such a first-in-class agent could be a valuable component of future combination therapies with increased cure-rates, shortened treatment times, and maybe without the need for current standard-of-care component ribavirin.


Curiously in light of these promising results, it appears as if GSK let an option to the Santaris compound expire. While Big Pharma may have multiple reasons why it does not want to pursue a certain compound aside from the science (e.g. the fact that HDL-cholesterol was lowered as a result of miR-122 inhibition could warrant caution), for example product portfolio considerations, one possibility is that IP concerns and GSK's relationship with Regulus were important factors: Regulus has an exclusive license to the IP surrounding the fundamental work by Jopling and Sarnow on the role of miR-122 in HCV replication. While this may be good news for Regulus, I was made aware that the broad Esau and Tuschl patent applications on microRNAs as therapeutic targets and held by Regulus are being narrowed down considerably by the patent offices.

Note: For a more detailed discussion of this paper, please read the review by Mark Kay and myself in Molecular Therapy (click here).


9 comments:

Anonymous said...

Hey!

awesome blog. I work with RNAi and parasitic nematodes, but its good to hear about different perspectives on the gene silencing front.

cheers.

Dr. T said...

The effect of SPC3649 on HCV sure is impressing.

However, what is not mentioned much is that there is a serious cancer risk associated with using SPC3649.

SPC3649 knocks out microRNA-122 which is a tumor suppressor negatively reulating a bunch of oncogenes - that will be up regulated by SPC3649.

The cancer risk has presumably also played into GSKs considerations when deciding not to exercise its option on SPC3649 for treatment of HCV.

Dirk, maybe you could comment on the link between microRNA-122 and cancer?

Dirk Haussecker said...

Dr. T.-
Thank you for your comment. I am not aware of experimental data showing a direct link of functional miR-122 depletion and liver cancer. Or has something occurred in the preclinical carcinogenicity studies or even the phase I safety trial that makes you think so?

Generally reduced function of microRNAs, however, is widely recognized to be associated with, and to be indeed promoting cancer development. Some of those studies have also been performed in liver. All this is consistent with the notion of one of the major functions of microRNAs being homeostatic regulation of the differentiated cell.

As to SPC3649 in chronic HCV infection, such a treatment would only be applied for a quite limited period of time...say around 12 weeks. As with other potential side effects of miR-122 antagonism, such as reducing HDL-cholesterol, the transient nature of the treatment should minimize the potential for severe adverse events.

Of course, given the very high abundance of miR-122 in the liver which one would think supports an important function for this microRNA, caution is warranted. An increased risk for cancer after anti-miR-122 treatment is certainly a valid hypothesis, and one of the things to be looked for. I would be happy, however, if you could provide me with the relevant references that would warrant GSK to drop SPC3649 based on this risk.

SK1 said...

Dirk, here is a bunch of references. I will leave the comments to you, besides noting that I wouldn’t want to be enrolled as healthy volunteer for phase 1 studies!

As for treatment, I think the duration of standard therapy with interferon and ribavirin is 48 weeks, which seems to be quite a while.

An insertion/deletion polymorphism at miRNA-122 binding site in the interleukin-1{alpha} 3' untranslated region confers risk for hepatocellular carcinoma.
Gao Y, He Y, Ding J, Wu K, Hu B, Liu Y, Wu Y, Guo B, Shen Y, Landi D, Landi S, Zhou Y, Liu H.
Carcinogenesis. 2009 Nov 16. [Epub ahead of print]PMID: 19917630 [PubMed - as supplied by publisher]

MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib.
Bai S, Nasser MW, Wang B, Hsu SH, Datta J, Kutay H, Yadav A, Nuovo G, Kumar P, Ghoshal K.
J Biol Chem. 2009 Nov 13;284(46):32015-27. Epub 2009 Sep 2.PMID: 19726678 [PubMed - in process]

Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties.
Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS.
Oncogene. 2009 Oct 8;28(40):3526-36. Epub 2009 Jul 20.PMID: 19617899 [PubMed - indexed for MEDLINE]Related articles

MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma.
Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, Lin CD, Liao YL, Wang JL, Chau YP, Hsu MT, Hsiao M, Huang HD, Tsou AP.
Hepatology. 2009 May;49(5):1571-82.PMID: 19296470 [PubMed - indexed for MEDLINE]

MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells.
Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, Calin GA, Grazi GL, Croce CM, Tavolari S, Chieco P, Negrini M, Bolondi L.
Cancer Res. 2009 Jul 15;69(14):5761-7. Epub 2009 Jul 7.PMID: 19584283 [PubMed - indexed for MEDLINE]Related articles

miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines.
Lin CJ, Gong HY, Tseng HC, Wang WL, Wu JL.
Biochem Biophys Res Commun. 2008 Oct 24;375(3):315-20. Epub 2008 Aug 8.PMID: 18692484 [PubMed - indexed for MEDLINE]

Downregulation of miR-122 in the rodent and human hepatocellular carcinomas.
Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K.
J Cell Biochem. 2006 Oct 15;99(3):671-8.PMID: 16924677 [PubMed - indexed for MEDLINE]

SK1 said...

Oh, I just changed my username; Dr. T = SK1

Dirk Haussecker said...

Dr.T- Without having read most of the referenced papers, I am aware of a few of those. I believe there had also been a Science paper that described AAV insertions into the miR-122 locus in new born mice with certain genetic background:

AAV Vector Integration Sites in Mouse Hepatocellular Carcinoma
Anthony Donsante, Daniel G. Miller, Yi Li, Carole Vogler, Elizabeth M. Brunt, David W. Russell, and Mark S. Sands
Science 27 July 2007 317: 477 [DOI: 10.1126/science.1142658] (in Brevia)

Considering all this, I must say I share your concern. My understanding is that a healthy liver with low regenerative cell division index should not be so much at risk (e.g. healthy volunteers in the phase I studies), however those with liver injury already predisposed to liver cancer are at an increased risk. You could argue, chronic HCV patients count among those.

Considering all this, I would argue not to give up on miR-122 for HCV esp. given a) none of this has been reported following miR-122 sequestration, and b) miR-122 targeting in HCV would likely be restricted up to around 12 weeks. Treatment failure patients could be the first population being considered, and if safety proves OK in real life, one could widen the candidate population.?

SK1 said...

I certainly agree not to give up on miR-122 for HCV, especially given the impressive chimp data. However, I would proceed with extreme caution, i.e. with extensive pre-clinical showing that sequestering mir-122 does not increase the risk of cancer. Even if it would occur very rarely, it would a be major problem. Liver cancer is usually really bad news, with a very short life expectancy...With HCV, you can live quite well for many years.

I have pasted a little text from some of the abstracts.

Hepatology. 2009 May;49(5):1571-82.
MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma.
Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, Lin CD, Liao YL, Wang JL, Chau YP, Hsu MT, Hsiao M, Huang HD, Tsou AP.
…. In this study, we show that liver-specific microRNA-122 (miR-122) is significantly down-regulated in liver cancers with intrahepatic metastasis and negatively regulates tumorigenesis. Restoration of miR-122 in metastatic Mahlavu and SK-HEP-1 cells significantly reduced in vitro migration, invasion, and anchorage-independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model….Thirty-two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell-cell signaling, and transcription…..Restoration of miR-122 has a far-reaching effect on the cell. Using the concomitant down-regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR-122 may prove to be beneficial for patients with hepatocellular carcinoma.

Oncogene. 2009 Oct 8;28(40):3526-36. Epub 2009 Jul 20.
Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties.
Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS.
… We report that miR-122 is specifically repressed in a subset of primary tumors that are characterized by poor prognosis. We further show that the loss of miR-122 expression in tumor cells segregates with specific gene expression profiles linked to cancer progression, namely the suppression of hepatic phenotype and the acquisition of invasive properties. ….. We further show that loss of miR-122 results in an increase of cell migration and invasion and that restoration of miR-122 reverses this phenotype. In conclusion, miR-122 is a marker of hepatocyte-specific differentiation and an important determinant in the control of cell migration and invasion…

Biol Chem. 2009 Nov 13;284(46):32015-27. Epub 2009 Sep 2.
MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib.
Bai S, Nasser MW, Wang B, Hsu SH, Datta J, Kutay H, Yadav A, Nuovo G, Kumar P, Ghoshal K.
The liver-specific microRNA-122 (miR-122) is frequently suppressed in primary hepatocellular carcinomas (HCCs). In situ hybridization demonstrated that miR-122 is abundantly expressed in hepatocytes but barely detectable in primary human HCCs. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and SK-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice…… Conversely, depletion of the endogenous miR-122 in Huh-7 cells facilitated their tumorigenic properties with concomitant up-regulation of these targets….. Collectively, these results suggest that the loss of multifunctional miR-122 contributes to the malignant phenotype of HCC cells, and miR-122 mimetic alone or in combination with anticancer drugs can be a promising therapeutic regimen against liver cancer.

Anonymous said...

Based on available data to date, is it possible to determine if Santaris' Locked Nucleic Acid approach to microRNA inhibition is more effective than the antisense approach used by Regulus/Isis?

Could Regulus/Isis pursue an LNA approach to microRNA inhibition without infringing Santaris patents?

What is the difference between the two methods?

Dirk Haussecker said...

I am not aware that Regulus has publicly announced the chemistry for their anti-miR122 compound. However, LNAs are a tough nut to crack at least in terms of affinity.

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