Biomedical Engineering Reference
In-Depth Information
treatment of topical, specifically ocular, diseases, but presently vigorous efforts are in
progress to cover the treatment of almost all the incurable diseases like cancer, hepati-
tis, AIDS, various other mutating viral diseases, and respiratory disorders, through vari-
ous routes of administration, including topical, inhalation, and systemic
[10,121-127]
.
Increasing figure of products in clinical and preclinical stages is a sign of foreseen break-
through in pharmaceutical and biotechnology market. Besides siRNA, a few other short
RNAs like miRNA and Piwi-associated RNA (piRNA) have also been identified
[128]
.
The folding of long single-stranded RNA sequences (encoded by specific genes and func-
tion in repressing mRNA translation or degradation) into intramolecular hairpins contain-
ing imperfectly base-paired segments led to the formation of miRNAs. piRNAs are also
from the long single-stranded precursors and its function is associated with Piwi subfam-
ily of Argonaute proteins. A large number of tiny noncoding RNAs have been discovered
since 1990, and this continues.
[126]
. Of these, siRNA was first identified because of
their potential to regulate gene expression. Recently, miRNAs have been shown to regu-
late critical biological processes from growth and development, to oncogenesis and host-
pathogen interaction in higher eukaryotes. miRNA is a natural molecule, also consisting
of dsRNA with short single-stranded ends. Primary miRNA is transcribed from DNA and
folds into a hairpin. The Drosha enzyme cuts the hairpin from the rest of the transcript,
forming pre-miRNA. The Dicer enzyme cuts away the loop, forming the mature double-
stranded miRNA. The double strand loads onto a ribonucleoprotein complex (miRNP),
which includes the Argonaute protein, and Argonaute cleaves one strand of the dsRNA,
incorporating the uncleaved single strand into the mature complex. This complex inhibits
translation of partially complementary mRNA
[128-130]
.
The behavior of the two classes, siRNA and miRNA, is the same. miRNAs are
encoded in the genome and are naturally used by cells to regulate gene expression.
siRNAs, on the other hand, are the affector molecules of the RNAi pathway and
are generated from the cleavage of dsRNA. Each can cleave perfectly complemen-
tary mRNA targets and decrease the expression of partially complementary targets.
However, the major difference between endogenous siRNA and miRNA (
Table 7.5
)
seems to be that the precursor of endogenous siRNA is a long dsRNA, whereas the
precursor of a miRNA is hairpin-shaped RNA.
Endogenous silencing small RNAs are termed miRNAs when they are genetically
encoded. They have the potential to arise from foldback structures characteristic of
miRNA precursor hairpins. siRNAs are similar small RNAs that do not appear to
correspond to protein-coding regions and do not have the potential to arise from hair-
pins characteristic of miRNA precursors, and yet they are expressed at sufficiently
high endogenous levels to be detected on RNA blots; there is a theory that they might
be processed from long dsRNA. As progress is made in understanding the role of
miRNA in biological milieu, these therapeutic molecules are promising for targeting
various diseases, including various neurodegenerative diseases that do not yet have
any effective therapies and conventional druggable targets. However, traditional anti-
sense and novel siRNA oligonucleotides or miRNA all typically need chemical mod-
ifications and formulation into clinically suitable, safe, and effective drug delivery
vehicles for stability and tissue targeting. To achieve this, it is essential to understand
the
in vivo
effect of these molecules.
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