Gene Delivery Using Physical Methods - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 95

Hydrodynamic gene delivery to organs other than the liver is mainly given
through efferent or afferent blood vessels, but this delivery route is complicated due
to the presence of guardian valves in vessels and the nonporous nature of target tis-
sues. Hydrodynamic gene delivery to a limb muscle of rat [26] and primate [72]
showed the same finding as in hydrodynamic gene delivery in the liver; that is, an
increase in injection volume increases gene expression, and an increase in injection
time decreases gene expression. In addition, the injection of vasodilator-like papava-
rine in limbs before hydrodynamic gene delivery increases the gene expression. The
hydrodynamic gene delivery to the kidney through a renal vein did not result in gene
expression compared to that in the liver [71] . Hydrodynamic gene delivery to the gut,
gonads, small intestine, and adrenal gland are under study [68,73] . The data suggest
liver and skeletal muscles as preferred organs for hydrodynamic gene delivery.
The in vivo transfection efficacy and simplicity of the hydrodynamic delivery sys-
tem made it the most useful method for delivery of compounds like siRNA for gene
slicing [90,103,104] , antigen as an immunomodulator [105-107] , DNA [108] , and
antibodies [74,102] . Nowadays, hydrodynamic delivery is most valuable in DNA and
RNA delivery. The hydrodynamic delivery method is most useful for the transfer of
the gene for therapeutic purpose in diseases like Fabry disease [109,110] , growth hor-
mone deficiency [111] , hemophilia [93,110,112,113] , metachromatic leukodystrophy
[114] , diabetes [115,116] , obesity [117,118] , myocarditis [119-121] , cytokine genes
[83,119-124,125] , and also in different types of cancer [83,106,119-121,123-134] .
Moreover, the hydrodynamic delivery method is also useful for transfection of cells
in whole animals, which will be helpful for analyzing the effect of transgene on vari-
ous physiological and biochemical processes occurring inside an animal [120] . In the
same fashion one can deliver the siRNA for target gene slicing and to downregulate
the functions associated with the target gene. In addition, the hydrodynamic delivery
method also helps to prolong the effect of therapy by repeated application. Moreover,
the hydrodynamic delivery method is also useful to carry out genomic studies in ani-
mals via in vivo transfection. For example, the successful establishment of a mouse
model of hepatitis B virus infection by bypassing many natural steps has been estab-
lished by hydrodynamic tail vein injection of the viral genome [135] . The expres-
sion of various genes like promoter strength [136-138] , intron sequences [139] ,
Epstein-Barr virus sequence [140,141] , and CpG sequences [110,142] is controlled
by a specific DNA fragment, which can be extensively examined by the hydrody-
namic delivery method in animals. Furthermore, the in vivo protein production can
be markedly modified by hydrodynamic gene delivery.
The application of the hydrodynamic gene delivery method has increased due to
advantages like efficacy and simplicity. However, some disadvantages, such as high
blood pressure, cardiac arrhythmia, damage to the target tissues due to high and rapid
pressure of injection, and toxicity of injected substances due to large injection vol-
ume, have limited the applicability of the hydrodynamic delivery system in clinical
practice. Further studies are required for justifying the basic mechanism of endothe-
lial tissue permeability and regulating injection volume and applied pressure during
hydrodynamic delivery. These are the major challenges for clinically efficient hydro-
dynamic gene delivery of therapeutics, which will increase its relevance in basic
research and the treatment of human diseases.