Antisense Oligonucleotides and RNA Interference - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 362

technology can be used to demonstrate the relative importance of various signaling
components at the molecular level in a controlled manner. Hence, this technology is
useful both in defining the role of a particular mediator in the process of inflammation
and in the screening of potential anti-inflammatory drugs [138,234,235] . The technol-
ogy has been reported to downregulate successfully the molecular targets involved in
various inflammatory diseases such as Crohn's disease [236] , inflammatory bowel dis-
ease [237] , renal allograft rejection [238] , and psoriasis [239] .
7.9.5 Respiratory Diseases
For the treatment of various diseases of the respiratory tract, novel respirable antisense
drugs called RASONS are used [240-242] . These RASONS can deliver antisense
medicines effectively and safely, even to deep lungs, by interacting with the unique
pulmonary surfactant of alveolar epithelial cells, resulting in enhanced cellular uptake
of the oligonucleotides. These are effective even at very low doses and can be delivered
using any of the delivery devices, whether nebulizer or dry powder inhaler or metered
dose inhalers. RASONS have been successfully used to treat respiratory diseases such
as asthma [240,242] , influenza [243] , bronchitis [242] , pulmonary fibrosis [242] , pneu-
monia [242] , and lung cancer [244] .
7.9.6 Cancer Chemotherapy
Numerous antisense drugs are currently being investigated to treat various cancers in
humans [245] . Here AS ODNs have the additional advantage of being less toxic than
conventional anticancerous medicines. A combination therapy of antisense drugs
with conventional medications may result in a reduction of dose and dose-related
side effects for both therapies. Phosphorothioates were the first AS ODNs to be used
in combination with cisplatin for the treatment of bladder cancer [246,247] . Since
then, several antisense drugs have been investigated for various cancers like colon
cancer [248,249] , lymphatic leukemia [250] , lung cancer [244,251] , testicular cancer
[252] , and lymphoma [250] .
7.9.7 Renal and Cardiovascular Diseases
AS ODNs can be used to target specific components in the blood vessel wall that
influence the pathophysiological mechanisms in renal and cardiovascular disorders.
Several reports document the role of the tissue kallikrein-kinin system in the patho-
genesis of hypertension. Reduced urinary kallikrein has been observed in hyperten-
sive subjects. Hence, systemic delivery of the human tissue kallikrein gene results in
a decrease in blood pressure and may assuage even glomerular sclerosis [253,254] .
However, antisense technology has been successfully used to elucidate the role of
tissue kallikrein-kinin system in blood pressure regulation. Intracerebroventricular
injection of AS ODNs against kininogen mRNA or bradykinin B 2 -receptor mRNA
results in an increase in blood pressure. However, injection of antisense against the
B 1 -receptor causes a decrease in blood pressure. Thus, antisense technology is useful