Biology Reference
In-Depth Information
proteins like the abovementioned lin-28 binding to the pri-miRNA
or pre-miRNA hairpin loops [
61
]. While their direct association in
human disease is evident, the profi ling of components of the
miRNA maturation pathway seems to be generally less specifi c and
predictive than the direct profi ling of miRNAs.
7
Therapeutic Approaches
There are different strategies for manipulating miRNA activity
with potential therapeutic signifi cance (
see
Chapter
3
and ref.
17
).
Among the different strategies, so far only the substitution or the
mimicking of aberrantly expressed miRNAs as well as the direct
complementary binding of mature miRNAs by anti-miRs or
antagomirs found their way into clinical trials. Antagomirs are a
special variation of antimirs, namely, chemically modifi ed single-
stranded RNA analogues targeting mature miRNA [
62
].
Intravenous administration of mir-122 antagomirs in mice
decreased corresponding miRNA levels in several organs in a spe-
cifi c, effi cient, and long-lasting manner. 2
-O-methyl oligoribonu-
cleotide antagomirs complementary to mir-122 were fi rst reported
to reduce cholesterol levels by down-regulating genes involved
into cholesterol biosynthesis which points towards new strategies
for gene regulation via miRNA silencing in disease.
The most promising study turned into clinical trial and has
fi nished phase two: the fi rst miRNA-targeting drug for treatment
of HCV infection [
63
]. The drug, called miravirsen, is the anti-
miR-122 oligonucleotide [
64
]. MiR-122 is involved in physiological
processes in hepatic function and also in liver pathology. It appears
to stimulate HCV replication through unusual interaction with
two binding sites of 5
′
-UTR in HCV genome; thus miR-122
silencing leads to inhibition of replication. On the other hand, loss
of miR-122 expression in hepatocellular carcinoma (HCC) points
to a poor prognosis and metastasis [
65
]. Remarkably, in case of
chronic lymphocytic leukemia (CLL) several targets of miR-122
could be identifi ed and proven to be involved in hepatocarcino-
genesis, among them serum response factor (SRF), insulin-like
growth factor 1 receptor, and cyclin G1. This bivalent behavior of
miR-122 demonstrates the complexity by which one miRNA can
be integrated into cellular pathways. Thereby it becomes an even
more interesting target for treatment of CLL and HCC, but might
also explain why it proves diffi cult to achieve effective conventional
therapy. There is a lot of effort directed towards miRNA-based
cancer treatment by several companies developing therapeutics
against different miRNA targets [
66
].
The search for RNA-based drugs includes not only miRNAs
but also antisense oligos, siRNAs, short hairpin RNAs, RNA
decoys, ribozymes, splice site-targeted oligos, and aptamers [
67
].
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