Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 294

drugs is limited [240] . Two important factors for graft failures are fibrointimal hyper-
plasia and subsequent graft atherosclerosis [241,242] . After graft implantation, a
process of medial smooth muscle cell (SMC) proliferation and migration begins in
response to growth factors and cytokines present in the complex biochemical milieu
of the healing graft, leading to a thick, circumferential neointimal layer. The initially
thin-walled vein is subjected to unusually high levels of tangential wall stress in the
higher pressure arterial environment, and neointimal wall thickening helps to reduce
this stress to near arterial levels [243] . The process of SMC formation expresses cyto-
kines, adhesion molecules, and chemoattractants leading to endothelial dysfunction
and accelerated atherogenesis in the graft wall [244] . One of the leading gene ther-
apy approaches for vein grafts is to prevent SMC migration and proliferation. Matrix
metalloproteinases (MMPs), including collagenases, stromelysins, gelatinases, and
membrane-type metalloproteinases (MT-MMPs), are upregulated following vascular
injury. Matrix remodeling using various MMPs is considered to be fundamental for
initiation of neointimal hyperplasia of vein grafts, allowing SMC migration. Four iso-
forms of endogenous tissue inhibitors of metalloproteinases (TIMP) have been identi-
fied. The Ad-mediated transfer of human TIMP-1 gene inhibited SMC migration and
neointimal formation in human saphenous veins [245] . Similarly, the overexpression
of TIMP-2 and TIMP-3 have shown promising results in human vein graft models,
with decreased SMC migration, gelatinolytic activity, and apoptosis [246,247] .
Because E2F transcription factor upregulates a dozen cell cycle genes, its inhi-
bition inhibits target cell cycle gene expression and DNA synthesis. The E2F tran-
scription factor blockage using decoy ODN showed promising results in clinical
trials [248] . Similarly, delivery of retinoblastoma resulted in attenuation of neointi-
mal thickening in experimental vein grafts by acting on E2F [249] . Soluble cell adhe-
sion molecules like VCAM-1 were delivered to inhibit leukocyte-released mitogenic
factors in porcine jugular and human saphenous veins [250] . Human senescent cell-
derived inhibitor gene-1 ( sdi-1 ), a mediator of the tumor suppressor p53 in cell cycle
and gene antisense to basic fibroblast growth factor (bFGF), resulted in the inhibi-
tion of neointimal hyperplasia in vein grafts [251] . eNOS is important to vascular
homeostasis and plays a vasoprotective role by inhibiting platelet and leukocyte adhe-
sion, inhibiting SMC proliferation and migration, and in turn promoting endothelial
survival. Nitric oxide (NO) bioactivity is substantially reduced and NO scavenging
superoxide is increased post-bypass graft surgery. Ad/nNOS gene transfer in a rab-
bit vein graft model favorably affected vein graft remodeling by inhibiting the early
inflammatory changes and reducing late intimal hyperplasia [252] . Similarly, in the
porcine vein graft model, Ad/iNOS resulted in inhibition of intimal hyperplasia [253] .
6.6 Applications of Gene Therapy in Kidney Diseases
Developments in the molecular characterization of the genetic defects associated with
renal disorders have stimulated research in using gene therapy for kidney diseases.
Gene delivery to the kidney has many advantages over other solid organs because of
its easy accessibility by many routes, including intrarenal artery infusion, retrograde