Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 296

that the delivery of C-myc AS-ODN into the polycystic kidney of the mouse model
improved renal function [260] .
6.6.1.3 Carbonic Anhydrase (CA) II Enzyme Deficiency and
Renal Tubular Acidosis
Renal acidosis is characterized by the inability to acidify urine and can be caused by
CAII deficiency, which is expressed in proximal tubules, loop of Henle, and interca-
lated cells of collecting ducts in healthy animals. As in humans, CAII-deficient mice
exhibit renal tubular acidosis manifested by growth retardation, low blood bicarbon-
ate, and inappropriately high urine pH at baseline and after acid challenge. In a study,
intrarenal injection of liposome was used to deliver human CAII cDNA under CMV
promoter in a CAII-deficient mouse. The results showed successful gene transfer
both at the levels of CAII mRNA and protein accumulation, with the peak at day 3,
and persisted for the entire 3-week duration of the study period [261] .
6.6.1.4 Nephrogenic Diabetes Insipidus
Congenital nephrogenic diabetes insipidus is an X-linked recessive disorder caused
by mutations in the vasopressin V2 receptor gene ( V2R ) rendering the renal collect-
ing ducts insensitive to the antidiuretic actions of the hormone arginine vasopressin
(AVP). A study using adenovirus-mediated delivery of the V2R gene restored the
normal functioning of the V2R under in vitro conditions [262] .
6.6.2 Glomerulonephritis and Renal Fibrosis
Glomerulonephritis is characterized by mesangial cell proliferation, extracellu-
lar matrix accumulation, and renal fibrosis leading to renal failure. A strategy was
designed to target mesangial cell growth using appropriated AS-ODN against platelet-
derived growth factor (PDGF) and transforming growth factor- (TGF-) genes, which
are responsible for mesangial cell growth and matrix deposition under experimen-
tal models [263] . The early growth response gene-1 (Egr-1) is a transcription factor
involved in mesangial proliferation of glomerulus. A study demonstrated that specific
inhibition of early growth response gene-1 (Egr-1) using AS-ODNs resulted in inhi-
bition of mesangial proliferation in glomerulonephritis model [264] . The AS-ODN
delivery of TGF- using hemagglutinating virus of Japan (HVJ) liposome in a unilat-
eral ureteral obstruction (UUO) model resulted in the prevention of acute tubulointer-
stitial fibrosis [265] . Double-stranded oligonucleotides containing elements to bind up
with a particular transcription factor, such as E2F and nuclear factor-B (NF-kB) decoy,
have also been utilized successfully in experimental glomerulonephritis by preventing
mesangial proliferation and extracellular matrix expansion [266,267] . DNA enzyme
against Ef06-01-9780123849649 has also shown beneficial effects in the interstitial
fibrosis UUO model, when delivered to the ureter through electroporation [268] .
The delivery of plasmid genes like decorin (a natural inhibitor against TGF-) [269]
and artificial soluble receptor for TGF- [270] prevented the matrix accumulation