Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 216

carcinoma in chronically infected individuals. The World Health
Organization (WHO) estimates that 3% of the world's population
is infected with HVC, with 170 million being chronically infected
[119]. The current treatments for HCV with pegylated IFN- α in
combination with ribavirin is only eff ective in about 50% of the
treated individuals and is associated with serious side eff ects [37,
94]. Therefore, RNAi therapy is being actively investigated as a
plausible treatment method for chronic HCV.
The positive-sense RNA genome of HCV is very similar to that
of other flaviviruses, but the 5 ′ UTR contains an internal ribosomal
entry site (IRES), which controls translation of the genome [75]. The
high conservation of the IRES makes it a good target for antisense
RNA-based therapies. For instance, i.v. administration of an antisense
oligonucleotide (ASO) ISIS 14803 targeting the IRES of the HCV
genome completed phase I clinical trials [87] although the phase II
trial was discontinued due to unsatisfactory results [50]. Along the
same lines, Santaris Pharma is testing an ASO (SPC3649) targeting
the cellular microRNA-122 (miR-122) as this miRNA is required for
efficient HCV replication [61]. In a recent publication, systemic i.v.
administration of SPC3649 at 5mg/kg in chimpanzees chronically
infected with HCV resulted in a significant decrease in serum HCV
RNA beginning 3 weeks after start of treatment and lasting several
weeks after cessation of treatment without inducing mutations in
the HCV RNA [73]. This ASO, which has been renamed Miravirsen,
completed a phase I clinical trial in September of 2010 [25] and
moved on to a phase II clinical trial where it is being administered
subcutaneously to chronic HCV patients [22].
Testing of RNAi-based antivirals to HCV has been slowed by
the absence of tractable small animal models. One study that came
closest to investigating RNAi control of viral hepatitis in vivo used
non-human primates infected with the closely related GB virus
(GBV)-B as a surrogate model for hepatitis C [129]. The significant
similarity between HCV and the flavivirus-like virus GBV-B at the
genomic and biochemical levels and the fact that intrahepatic
inoculation of new world monkeys like tamarins and marmosets
with GBV-B RNA establishes persistent infection with chronic
hepatic inflammation, both of which are key features of hepatitis C
infection, has led to the proposal of the GBV-B/monkey system as
a good surrogate model for hepatitis C [85]. Administration into
marmosets of cationic liposome-encapsulated siRNA targeting the