Biomedical Engineering Reference
In-Depth Information
to large families with closely related subtypes and isoforms are generally nondis-
tinguishable using common assay techniques. By using AS ODNs that can bind
to one specific subtype, however, it is possible to distinguish them, as a sufficient
degree of diversity exists in the mRNA sequences of these closely related proteins.
Phosphodiester oligonucleotides exhibit considerably more stability in cerebrospinal
fluid (CSF) than in plasma but require frequent administrations in large quantity to
obtain significant antisense inhibitory effects [215] . Phosphorothioate oligonucle-
otides, though having good stability in CSF and producing the desired antisense
effect, are quite toxic [216,217] . AS ODNs exert their inhibitory effect through
RNase H mechanisms in the brain [218] . PNAs and LNAs have also been tried to
inhibit inappropriate protein expression [219,220] . As AS ODNs cannot readily cross
the blood-brain barrier, invasive methods such as intraventricular, intraparenchymal,
and intrathecal administrations have also been tried to deliver AS ODNs to the brain,
but these result in tissue injury and hemorrhage [142,221] . Antisense technology has
been reported to treat brain disorders such as Alzheimer's disease [222,223] , pain
[224,225] , and affective disorders [226] successfully.
7.9.3  Inhibition of Specific Enzymes or Receptors
Being selective and specific, AS ODNs can be readily used to inhibit expression of a
particular enzyme or a receptor belonging to a large family with closely related sub-
types. Inhibition of acetyl cholinesterase enzyme is the molecular target for the treat-
ment of diseases like Alzheimer's disease [227] and myasthenia gravis [228] . Advances
in research concerning Alzheimer's disease and myasthenia gravis have demonstrated
alternative splicing variants of acetyl cholinesterase enzyme being involved in the eti-
ology of these diseases. Thus, only AS ODN therapy could be useful in the manage-
ment of these diseases. AS ODNs have also been used successfully to characterize
the various members of D 2 dopamine receptors [229] . This technology has also been
employed to differentiate between different opioid receptors viz . mu, delta, and kappa
[230] . Similarly, AS ODNs have been successfully utilized to study the various phos-
phatases involved in cellular growth-control pathways and thus help in the screening
of potential anticancerous agents [231-233] . These enzymes regulate diverse cellular
processes such as metabolism, ion-channel activity, and membrane transport as well as
learning and memory. Thus, inhibition of many protein kinases using AS ODNs have
been used to treat related disorders in humans.
7.9.4  Inflammatory Diseases
Inflammation is the body's protective response to physical or microbial threat, char-
acterized by redness, swelling, heat, and pain; it results in increased blood flow,
increased capillary permeability, plasma protein leakage, and migration of leukocytes
to the site of injury. When inflammation is deregulated, disease or even death can hap-
pen. In acute inflammatory processes cells like eosinophils, neutrophils, monocytes,
and macrophages migrate to the site of injury in response to chemotactic factors such
as platelet-activating factor, leukotrienes, and cytokines. In inflammation, antisense
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