Biomedical Engineering Reference
In-Depth Information
of the donor heart at the time of removal offers the unique opportunity to produce
a therapeutic molecule within the graft itself, while minimizing systemic effects.
Cytoprotective approaches including gene transfer of HO-1, endothelial nitric
oxide synthase, and antisense oligodeoxynucleotides specific for nuclear factor
(NF)-kappa B or intercellular adhesion molecule (ICAM)-1 reduced ischemia-
reperfusion injury and delayed cardiac allograft rejection in small animals.
Exogenous overexpression of immunomodulatory cytokines such as interleukin
(IL)-4, IL-10 and TGF-b, as well as gene transfer of inhibitors of pro-inflammatory
cytokines also delayed graft rejection. Gene transfer-based blockade of T-cell
costimulatory activation with CTLA4-Ig or CD40-Ig has resulted in long-lasting
graft survival and donor-specific unresponsiveness, as manifested by acceptance of
a second graft from the original donor strain but rejection of third-party grafts.
Similar results were obtained with donor major histocompatibility complex class I
gene transfer into bone marrow cells. Gene therapy approaches to chronic rejection
included gene transfer of HO-1, soluble Fas, tissue plasminogen activator, and
antisense oligodeoxynucleotides specific for the anti-apoptotic mediator Bcl-x or
the E2F transcription factor. Despite major experimental advances, however, gene
therapy for heart transplantation has not entered the clinical arena yet. Fundamental
questions regarding the most suitable vector, the best gene, and safety issues remain
unanswered. Well-controlled studies that compare gene therapy with established
treatments in nonhuman primates are needed before clinical trials can be started.
Gene Therapy for Peripheral Arterial Disease
Angiogenesis by Gene Therapy
Therapeutic angiogenesis is a novel strategy for the treatment of limb ischemia.
Recombinant angiogenic factors such as FGF have been used to augment collateral
artery development in animal models of myocardial and hind limb ischemia.
Adenovirus-delivered FGF-4 (Ad5FGF-4) by intramuscular injection has been
studied in a small series of patients with critical limb ischemia. Ad5FGF-4 seems
safe, but transfection efficacy is limited at the assessed doses and conclusions
regarding clinical efficacy cannot be drawn from the small number of patients studied
(Matyas et al.
2005
).
VEGF stimulates angiogenesis, and protocols for therapeutic angiogenesis by
gene transfer in patients with PAD have been presented. The technique involves site-
specific transfer of plasmid DNA encoding the VEGF.
HIF-1a Gene Therapy for Peripheral Arterial Disease
Ischemia is a stimulus for production of angiogenic cytokines that activate local
vascular cells and mobilize angiogenic cells to the circulation. These responses are
impaired in patients with peripheral arterial disease. Hypoxia-inducible factor
(HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic
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