Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 298

Si-RNA targeting Fas has shown promising results in mouse model of ischemia
reperfusion both by local renal vein injection and systemic administration [286] .
6.6.3.3 Gene Therapy for Chronic Renal Transplant Dysfunction
A number of factors such as immune-mediated damage of the renal graft, acute rejec-
tion episodes, ischemia-reperfusion injury, donor and recipient morbidity, and viral
infections have been implicated in the development of chronic transplant dysfunction.
All these factors result in progressive loss of renal graft function, associated with pro-
teinuria and hypertension, and histopathologically in tubulointerstitial infiltrate with
monocytes and T-cells, tubulo-interstitial fibrosis, glomerulopathy, and vascular inti-
mal hyperplasia [287] .
Attempts have been made to modulate the immune response to prevent chronic
allograft rejection. In a study, adeno-associated virus-mediated CTLA4Ig gene trans-
fer protected MHC-mismatched renal allografts from chronic failure [288] . The
macrophages activity is one the major causes for chronic transplant dysfunction.
Targeting of macrophage activity by adenovirus-mediated intragraft overexpression
of TNFRp55-Ig (TNF receptor p55 immunoglobulin), IL-12p40, and vIL-10 amelio-
rates adenovirus-mediated chronic graft injury in the rat allograft model [289] . HGF
was also used for chronic renal dysfunction due to its antifibrogenic and antiinflam-
matory effects [290] .
6.7 Applications of Gene Therapy in Gaucher Disease
Gaucher disease (GD) is an inherited, autosomal recessive, most common lysosomal
storage disorder characterized by a decreased level of enzyme -glucosidase (gluco-
cerebrosidase). The mutations in the gene called acid -glucosidase result in defec-
tive synthesis of enzyme glucocerebrosidase, leading to the accumulation of lipids
called glucocerebrosides in macrophages [291] . These glucocerebrosides-laden mac-
rophages are known as “Gaucher cells,” and are the classical hallmark of the disease.
Gaucher cells are large, wrinkled-appearing cells that store glycolipids, and they are
usually found in the BM and the spleen [292,293] .
Enzyme replacement therapy (ERT) is the standard treatment for GD. However,
it is very expensive to administer biweekly infusions of the recombinant enzyme
throughout the life of the patients [294,295] . Another therapeutic option is to
decrease the synthesis of glucosylceramide, using inhibitors of ceramide glucosyl-
transferase, that is, substrate reduction therapy (SRT), but this strategy appears to be
more toxic and less effective than ERT [296,297] .
6.7.1 Preclinical Studies
Gene therapy could provide an alternative for GD by delivering the glucocerebrosi-
dase (GC) gene using vectors ex vivo and in vivo . In a study, insertion of the human
GCcDNA into mouse fibroblasts resulted in the appearance of human enzyme activity.