|
 Investigator:
Craig Tisher
Diabetic renal disease is the leading cause of end-stage
renal failure (ESRF) in the western world accounting for / approximately
39% of all patients with ESRF .At present almost 45,000 patients
with ESRF are awaiting a kidney transplant in this country but on
average only 12,000 patients receive a graft each year. Another
cause of ESRF is graft loss in the kidney transplant recipient.
Although most kidney transplant centers can achieve a l-year cadaveric
allograft survival of 85 to 90%, only approximately 50% of the kidneys
function at 7 years and 20% at 10 years. In all kidney transplant
recipients but especially in those with underlying diabetes mellitus,
disease of the arterial vessels in the kidney and especially of
the endothelial cells that line the vessels and the smooth muscle
cells that are located in the wall of the vessels can eventually
lead to ESRF.
Three of the major factors that initiate vascular
injury include acute and chronic immune injury , cyclosporine and
FK506 nephrotoxicity and hypertension. As a response to these injurious
agents, the endothelial and smooth muscle cells proliferate, so-called
myointimal proliferation. Over time this leads to narrowing of the
vascular lumen, chronic ischemia and renal fibrosis with loss of
kidney function. In the diabetic patient recurrent vascular disease
in the form of subintimal hyaline arteriolosclerosis also contributes
to the vascular injury to the kidney. Interruption of this vicious
cycle could greatly prolong the life of a kidney allograft and reduce
the need for second and third kidney transplants. Angiostatin is
a protein found in small amounts in the blood that has been shown
recently to inhibit proliferation of endothelial and smooth muscle
cells. We have demonstrated recently that the gene responsible for
producing this protein can be introduced into endothelial cells
both in vitro and in vivo.
Using gene therapy techniques common to our laboratory,
we propose to insert the gene into the endothelial and smooth muscle
cells in the vessels of the transplanted kidney at the time of surgery
to enhance the secretion of angiostatin and thereby prevent the
myointimal proliferation that leads to eventual loss of the transplanted
organ. Initial studies will be conducted in the rat. If these are
successful, the next step would involve the conduct of similar I
procedures in subhuman primates with the ultimate goal of introducing
this form of gene therapy to patients undergoing kidney transplantation.
|
