Biology Reference
In-Depth Information
Most demanding challenge in drug development is to address the
desired tissue, because drug delivery is not always effi cient enough.
Normally, oligos do not cross the blood-brain barrier and do not
enter heart or muscle. Several tissues though can be reached by
simply injecting the drug into the bloodstream. Another way is the
subcutaneous administration, which localizes the drug for example
in liver, kidney, and fat. Besides delivery issues, most concerns
direct towards off-target effects and immune responses caused by
treatment but do not seem to be insuperable. A very elegant pos-
sibility is local drug delivery, for example to the eye or the lung.
The fi rst RNA-based drug, called fomivirsen, is used to treat
infl ammation of the eye that is caused by cytomegalovirus. It is an
antisense oligo that inhibits target gene expression [
68
,
69
].
Despite using oligonucleotides or sponges targeting
mature
miRNA, some other approaches to interfere with miRNA matu-
ration
itself
are obviating access amounts of miRNA. Hence,
upstream regulation may be the even better choice of contact
point. One possibility to inhibit Dicer-mediated cleavage by spe-
cifi cally binding pre-miRNAs is realized by fi nding RNA-binding
small molecules [
70
-
72
]. Recently, Maiti et al. found a specifi c
inhibitory activity on miR-21 maturation for the antituberculosis
drug streptomycin [
73
]. A completely different, but maybe even
more promising, strategy has been developed by Deiters et al. They
made use of a luciferase-based miRNA reporter plasmid that after
transcription yields an mRNA comprising miRNA-binding site in
3
-UTR [
74
]. Two independent screens identifi ed small molecules
which lead to reduced miRNA expression in living cells and pre-
sumably act upstream pri-miRNA formation [
75
,
76
]. Such
approaches imply that the drawbacks of nucleic acid-based drugs
may be circumvented in the future.
′
8
Conclusion
To sum up, miRNA maturation is a potent target in cancer diag-
nostics and therapy, because changes in the expression pattern of
miRNA correlate with abnormal cell growing which often leads to
cancer. But there also is a variety of other human diseases certain
miRNAs are linked to, including viral infections, neurodegenera-
tive diseases, and diabetes. miRNAs involved in cancerogenesis
either act as tumor suppressors or apoptotic inhibitors; hence they
are aberrant or excrescent in cancer cells, respectively. The origin of
abnormal mRNA processing may be found in two different levels
of deregulation, which are miRNA transcription and miRNA
maturation. Naturally, there is a need for adequate assays to detect
changes in miRNA maturation and following change in expression
patterns. One step to fully understand correlation between disease
and miRNA levels is to determine the abnormal point of change on
