Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 295

delivery through the urinary tract, and direct injection into renal parenchyma; the
effect of the therapeutic molecule is limited in the kidney; and the harmful effects
to other tissues can presumably be limited [254] . However, many physiological fac-
tors such as cell turnover rate, blood flow, and urine flow, as well as anatomical fac-
tors such as glomerular basement membrane and nephron segment arrangement, may
affect the specificity and efficacy of gene therapy in the kidney. Until now, there has
been no renal gene therapy available for clinical use; however, gene therapy for sev-
eral experimental renal diseases has been tested with promising results. Gene therapy
for some monogenetic and acquired renal diseases is discussed briefly below.
6.6.1 Monogenetic Hereditary Renal Diseases
The various monogenetic kidney disorders for which gene therapy trials have been
conducted in experimental models are Alport syndrome, autosomal-dominant poly-
cystic kidney disease, aquaporin (AQP) I deficiency and concentrating ability defect,
carbonic anhydrase (CA) II enzyme deficiency, and renal tubular acidosis [255] .
6.6.1.1 Alport Syndrome
Alport syndrome is caused by a defective structure of the type IV collagen frame-
work of the glomerular basement membrane [256] . Type IV collagen is a triple-heli-
cal protein consisting of three chains: 3(IV), 4(IV), and 5(IV). In most of the
cases, it is caused by mutations in the X-chromosomal gene encoding the 5(IV)
collagen chain ( COL4A5 ). This leads to disassembling of the adult-type glomerular
basement membrane and the embryonic-type glomerular basement membrane substi-
tutes, resulting in reduced mechanical strength of the collagen framework as a filter
and its sufficient resistance against proteolysis. The syndrome is inherited glomer-
ulonephritis and is characterized by hematuria and proteinuria consequences in the
deterioration of structure and the development of progressive renal failure. The first
study for Alport syndrome utilized a perfusion of Ad vector for 2-12 h, which allows
gene transfer exclusively to glomerular cells. The results showed successful delivery
of COL4A5 to glomerular cells of kidneys [257] . Furthermore, in a study, of adeno-
virus-mediated perfusion in the canine model Alport syndrome, the introduced gene
for a5(IV) collagen expressed in the glomeruli and assembled triple-helical type IV
collagen fiber composed of 3(IV), 4(IV), and 5(IV) [258] .
6.6.1.2 Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Generally, the concept of gene therapy is limited to gene replacement in autosomal
recessive diseases. Therefore, ADPKD may not be the normal target for the gene ther-
apy. However, the two genes identified as responsible for ADPKD are pkd1 and pkd2 .
The main strategy in the gene therapy of ADPKD is to prevent the increase in the
size of the cyst. An in vivo study conducted using adenoviral-mediated -galactosi-
dase gene delivery into the mouse model resulted in the expression of -galactosidase
in epithelial cells of cyst and surrounding fibroblasts [259] . Another study showed