Great ape protection act

chimpanzee HamI received the following email today from Judith S. Bond, President of the Federation of American Societies for Experimental Biology (FASEB):

Dear Colleague,

We need your help to counter a serious threat to the humane use of animals in research. The Great Ape Protection and Cost Savings Act (S 810), which would prohibit the use of chimpanzees in medical research, may be voted on in the Senate this week (it was approved by a Senate committee in July)! Passage of this bill could have devastating consequences for ongoing research into human diseases such as hepatitis C, as well as studies benefiting the great apes themselves. Even if you do not work with great apes, you should be concerned about this bill because it would end research deemed by the Institute of Medicine (IOM) to be ethically sound and scientifically important and could pave the way for legislation to ban research with other species

Those who oppose the use of animals in research are making an aggressive effort to get this bill passed before Congress goes home for the year. We must let them know that chimpanzees are important animal models for research. Please take action now by going to to send an email to your Senators urging them to oppose the Great Ape Protection and Cost Savings Act.

You can find the text of this bill on this webpage (the pdf link at the top of the page provides the most readable version of the bill). Great apes include the chimpanzee, bonobo, gorilla, orangutan, and gibbon. Invasive research is any research that may cause death, injury, pain, distress, fear, or trauma.

According to the text of the bill, the chimpanzee is the only great ape used for invasive research in the United States, where there are approximately 1000 housed in laboratories.

The bill cites the Institute of Medicine and National Research Council report entitled “Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity” which concluded that most current use of chimpanzees for biomedical research is unnecessary.  It states that research on hepatitis C antiviral drugs, respiratory syncytial virus, future monoclonal antibody therapies, or a therapeutic hepatitis C virus vaccine, does not require chimpanzees, and that ‘the use of a combination of non-chimpanzee methods for the development of monoclonal antibody therapies may make research on the chimpanzee largely unnecessary; and non-chimpanzee models, if further improved, may reduce or obviate the need for the continued use of the chimpanzee for prophylactic hepatitis C vaccine research.’

Presumably the authors of the bill refer in part to work directed on developing a mouse model for HCV infection. However, as indicated by the bill’s language, it is not yet clear if these models will supplant the chimpanzee for HCV research.

The purpose of this act is to phase out invasive research on great apes and the use of Federal funding of that research, both in and outside of the United States. All existing chimpanzee protocols must be terminated within three years of passing of the bill, and once the bill has been passed, no new chimpanzee experiments may be started.

There is an escape clause – if, after three years have passed, it is determined that a new disease requires research on chimpanzees, the Great Ape Task Force will be created to evaluate that need.

If this act had been passed in the 1950s, it might not have been possible to develop poliovirus vaccines. While transgenic mice recapitulate much of poliovirus pathogenesis, they are not orally susceptible to infection (unless the interferon system is disabled) and therefore cannot reliably be used to test protection conferred by immunization.

It seems premature to pass an act banning research on chimpanzees. These animals are needed for testing anti-HCV therapies and vaccines, and as stated in the bill, it is not yet clear if other animal models will replace chimpanzees. It seems prudent to wait until we have a suitable animal model for HCV (and other infectious and non-infectious diseases which currently require chimpanzees) before outlawing the use of this animal in research.

New hepatitis C antiviral drugs

chlorocebus-pygerythrusNearly 3% of the world’s population – about 175,000,000 individuals – are infected with hepatitis C virus (HCV), and 3-4 million new infections are added each year. A high percentage of these become life long, chronic infections, which may lead to cirrhosis, hepatocellular carcinoma, and death. No vaccine is available, and the only antiviral treatment, pegylated interferon plus ribavirin, is often ineffective and has adverse side effects. The extent and severity of hepatitis C has stimulated the development of many new antiviral compounds, including protease and polymerase inhibitors. Perhaps one of the most unusual treatments being considered is one that directly targets a small RNA, known as a microRNA (miRNA), that is abundant in the liver.

Micro RNAs are single-stranded RNA molecules 21-23 nucleotides long which regulate the expression of about 30% of all mammalian protein-coding genes. They act by binding to the 3′-non coding region of mRNAs which leads to degradation of the mRNA or inhibition of translation. When miRNAs were first discovered, many virologists searched for target sequences in viral genomes to discover new ways to inhibit viral replication. A binding site for a liver-specific miRNA, called miR-122, was found in the RNA genome of HCV. However the target site for miR-122 was found in the 5′-noncoding region of the mRNA, not in the 3′-end. To the investigators’ surprise, binding of miR-122 to the HCV RNA stimulated viral replication. HCV replication in cells lacking miR-122 is significantly reduced compared with cells that produce miR-122.

The requirement of miR-122 for HCV replication suggested that this miRNA could be a target for therapeutic intervention. One approach has been the use of antagomirs, which are small synthetic RNAs that are complementary to the miRNA target. By binding to the miRNA, antagomirs block their ability to bind the target sequence and inhibit their function. An antagomir to miR-122 was found to impair HCV replication in cultured liver cells. Last year, a phase I clinical trial of an miR-122 antagomir was initiated in humans.

An important question is whether inhibition of miR-122 influences the expression of cellular genes which might lead to adverse side effects. If the antagomir is ever licensed, it will have another benefit besides inhibiting HCV replication: reduced cholesterol levels. miR-122 is believed to be involved in the regulation of cholesterol, fatty acid, and lipid metabolism, and African green monkeys who were administered the miR-122 antagomir had reduced plasma cholesterol.

C. L. Jopling, MinKyung Yi, Alissa M. Lancaster, Stanley M. Lemon, Peter Sarnow (2005). Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA Science, 309 (5740), 1577-1581 DOI: 10.1126/science.1113329

Jan Krützfeldt, Nikolaus Rajewsky, Ravi Braich, Kallanthottathil G. Rajeev, Thomas Tuschl, Muthiah Manoharan, Markus Stoffel (2005). Silencing of microRNAs in vivo with ‘antagomirs’ Nature, 438 (7068), 685-689 DOI: 10.1038/nature04303

Y SHAN, J ZHENG, R LAMBRECHT, H BONKOVSKY (2007). Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes Gastroenterology, 133 (4), 1166-1174 DOI: 10.1053/j.gastro.2007.08.002

Joacim Elmén, Morten Lindow, Sylvia Schütz, Matthew Lawrence, Andreas Petri, Susanna Obad, Marie Lindholm, Maj Hedtjärn, Henrik Frydenlund Hansen, Urs Berger, Steven Gullans, Phil Kearney, Peter Sarnow, Ellen Marie Straarup, Sakari Kauppinen (2008). LNA-mediated microRNA silencing in non-human primates Nature, 452 (7189), 896-899 DOI: 10.1038/nature06783