In siRNA that act with greater efficiency and in

In the modern era of science, human discovered
lots of techniques and tools to avoid the malady. Over
the last past two decades, the uses of nucleic acid based therapy move toward,
which approaches to knockdown the gene expression.  First wave toward of gene silencing came in
the 1980s as synthetic DNA chemistry, antisense oligodeoxy-ribonucleicacid
(ODNs) that down regulate gene expression by sequence specific manner (Agrawal and
Kandimalla, 2000). Second move has been the exploitation of catalytic nucleic acid
biology followed the discoveries of ribozymes (Cech et al.,
1981; Guerrier-Takada
et al., 1983). The
third explosive RNA interference (RNAi) pathway from the discoveries of Mello
and colleagues in  Caenorhabditis elegans in 1998 (Fire et al.,
1998), and subsequently
in mammalian cells (Elbashir et
al., 2001a).

 RNAi, participates
in regulation of gene expression that limits the transcript level by either
suppressing transcription or by activating a sequence-specific RNA degradation
process (Hammond et
al., 2001; Sharp, 1999). It promises
as a powerful research gizmo, not only involves in several active endogenous
role, moreover, reducing the gene expression for therapeutic purposes in biological
science. (Hamilton and
Baulcombe, 1999). Additionally it also participates to regulate the development of
an organism with proper function of its cells and tissues. Besides knockdown
the gene expression, RNAi also play a vital role in chromosomal remodeling (Sioud and
Leirdal, 2000). The
first reported experiments of RNAi mediated systemic long-lasting
silencing in Caenorhabditis
elegans demonstrated as a response induced by double-stranded RNA (dsRNA)
molecules (Timmons and
Fire, 1998).

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Small interfering RNA (siRNA) is one of the most recent achievement
 to the repertoire of sequence specific
gene silencing agents (Wassenegger
et al., 1994) and
the effectors molecules of the RNAi pathway (Miller et
al., 2003; Rodriguez-Lebron
and Paulson, 2006). siRNA
that act with greater efficiency and in a highly specific manner, appeared to
be standard and reliable method; compared to single-stranded antisense RNA,
only a fraction of siRNA  were required
to alter the gene expression. It is like a multitasking device for the biological
functions not only evolutionary conserved regulatory mechanism in organisms as
diverse as plants (Dorsett and
Tuschl, 2004) and
mammals (Hammond et
al., 2001) but
also defending against parasitic genes and viral RNA or transposon (Ghildiyal et
al., 2008). It
opens the way to explore the new avenue for pest and disease resistance. Likewise
also play crucial role for abiotic, drought, salt, mechanical, cold/heat and UV-B
radiation stress tolerance plants and good crop quality 25332689 as a promising biopesticide. 27941836. Down regulation of the expression of toxic
genes by RNAi technology that acts with greater specificity is a kind of highly
efficient machinery and it facilitate a functional mode for genetic improvement
with low genetic transformation capability in plants (Ogita et al.,
2003). A
mutant line of rice LGC-1 (Low Glutelin Content-1) was the first commercially
useful cultivar produced by RNAi (Kusaba et
al., 2003). In
Arabidopsis thaliana, multiple dicer, which is an RNase III family enzyme,
initiates the RNAi, specifically act against different viruses and other
foreign genetic material, sometimes also show an adaptive immune response
against viruses through this machinery (Takeda et
al., 2005).

 In this view RNAi
technology has surfaced as an attractive therapeutic approach to achieve
treatment for progressive and untreatable fatal diseases. Strategy of RNAi have
worldwide used for basic research, and are now emergent tools to induce for remedial
purposes. RNAi in the central nervous system (CNS) positively has enormous approaches
for genetic medication as well as genomic studies. Many of the major
neurological diseases that are noteworthy causes of mortality are likely to be appropriate
targets for therapeutic gene silencing; these include CNS tumors and
neurodegenerative disorders (Barchet and
Amiji, 2009). Bioinformatics
and reporter gene experiments foretell that up to 1/3 of the genes in the human
genome may be regulated by the RNAi pathways (Schwarz et
al., 2003).  RNAi technology have emergent therapeutic tool
and the natural functions of this pathway such as gene regulation and the
control of chromatin structure and function are conceivable (Dernburg and
Karpen, 2002). Here
is a brief description of RNAi technology, dealing with neurological disorders as
trinucleotide repeat diseases, alzheimer’s disease (Miller et
al., 2004), CNS
tumors, prion diseases (Tilly et al.,
2003), huntington
disease and several spinocerebellar ataxia (SCA types1, 2, 3, 6, 7 and 17). Moreover
another class of neurological diseases also have therapeutic target of RNAi  like  parkinson
disease, dystonia, (Miller et
al., 2005) slow
channel congenital myasthenic syndrome, (Abdelgany et
al., 2003) and frontotemporal
dementia, which caused by overexpression of CAG-repeat expansions / mutated
gene (Jana et al.,
2004). In short
RNAi has been regarded as a revolutionary molecular tool, used to detect the function
and location of the gene as well as triggering gene silencing promise as
therapeutic applications.


silencing approaches

In the last few years of molecular research different types of molecules
are introduced that act to down regulate the gene expression.  In this concern application of nucleic acid
based technologies are come in the stage. To manipulate the gene expression by
sequence specific manner targeting of mRNAs have been developing in the hope of
creating therapeutic agents. Three main nucleic acid based gene-silencing
molecules are- chemically modified antisense oligodeoxyribonucleicacid (ODNs),  ribozymes and siRNA (Houlden et
al., 2001).


Antisence ODNs

ODNs are generally 18–25 bases in length (Zhang et al.,
2005). The
mechanisms of action of ODNs to down regulate the gene function and diminish
the translation of target proteins, elicit RNAs-H mediated cleavage of the
target mRNA (Scherer and
Rossi, 2003). Numbers
of chemical modifications were developed to improve the stability of ODNs in terms
of nuclease resistance and specific binding (Miyake et
al., 2011).

 The first, second and third
generation of antisense agents contains backbone modifications, substitutions
of position 2′ of ribose with an alkoxyl group and contains structural
elements, such as zwitterionic oligonucleotides respectively (Mansoor and Melendez,
2008). The
most widely used back bone modification is one in which the non-bridging oxygen
is replaced by a sulphur atom, creating phosphorothioate ODNs (Li et al.,
2006) to
add to their effectiveness.



Ribozyme (RZ) are RNA molecules that act as enzyme bind to RNA
through Watson– Crick base pairing to degrade target RNA by catalyzing the
hydrolysis of the phosphodiester backbone (Doudna and
Cech, 2002). Few
examples of the wide spectrum of RZ in which ‘hammerhead’ ribozyme, composed of
approximate 30 nucleotide being the most widely studied  (Haseloff and
Gerlach, 1988). It
can be applicable to cleave any specific target by modifying the arms that base
pair with the target (Berry et al.,
2001). Ribozymes can be delivered via vectors or
plasmid and the expression controlled by promoter.