Friday, June 8, 2007

Adding RNAi to the Arsenal in the Fight against Hepatitis C

170 million people worldwide are infected with the Hepatitis C virus. Hep C, an RNA virus, is emerging as a significant public health problem that is only set to grow exponentially as many chronic carriers are about to develop liver cirrhosis and cancer after having been infected for a number of years.

Currently, treatment options for Hep C are essentially limited to a combination of interferon and ribavirin, both antivirals of which the mechanism of action is not completely understood. However, the need for additional treatment options has never been greater. While about 50% of those who adhere to treatment will be “cured” of the virus, many that start therapy do not complete the full treatment regimen due to the sometimes severe side-effect profile and the need for prolonged treatment.

The good news is that there is a whole generation of promising new drugs currently in pre-clinical and clinical development that target the virus directly. The most advanced of these are small molecule inhibitors of the Hep C protease and polymerase, some of which are about to enter phase III clinical trials. Early experience with Vertex Pharmaceutical’s VX-950 e.g. has shown impressive response rates of around 80-90% and reductions in viral loads and is expected to become an important part of future treatment strategies, mostly likely involving combination therapy due to viral resistance. Nevertheless, some of these drugs did not prove efficacious or safe and were discontinued. Morever, those drugs that will get approval will not work in every patient due to variability of the genetic background of the host (=patient) and the virus, and still more treatment options are desirable.

RNAi, through its ability to target the RNA genome of the virus itself, offers a unique opportunity in helping close that gap further. Its unique mechanism of action should contribute to shortening the course of treatment and enhancing response rates. Curiously, Hep C’s cousin, the Hepatitis B virus, was the first virus for which in vivo efficacy of RNAi was demonstrated. This is because of a lack of a good animal model system for Hep C that led a number of groups to target Hep B as a model system for Hep C RNAi treatments as both viruses share the same host tissue and delivery is considered as the main hurdle to achieve treatment success of RNAi. Despite the early promise, corporate actions, however, now seem to have put Hep C RNAi on the backburner.

Before being aquired by Merck, Sirna Therapeutics with the help of Protiva scientists demonstrated promising knockdown of Hep B in mice using the SNALP-siRNA delivery system. They even presented non-human primate Hep C data during corporate presentations and claimed treatment success in a limited number of animals. Progress, however, seems to have stalled as a result of a legal dispute surrounding the SNALP delivery system. Another sorry example is Benitec which had plans to progress a Hep C program, most likely involving a cocktail of DNA-directed shRNAs, to the clinic this year. As funding ran out and the company was forced to move back to Australia, management decided to spin off the Hep C program to a new company, Tacere, which, also short of money, is now struggling to extract any value out of the Hep C program.

It can only be hoped that the potential of RNAi for Hep C is not forgotten. Certainly, qualified academicians, clinicians, RNAi delivery systems, and RNAi targets are all there and waiting. The trick is to bring them together and give them funding to get on with what they are best at.

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By Dirk Haussecker. All rights reserved.

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