1868: Prevention of Chronic Allograft Nephropathy(CAN) With Hepatocyte Growth Factor (HGF) Gene Transfer

Abstract. Long-term renal isografts in humans and laboratory animals exhibit features similar to those of chronic allograft nephropathy (CAN), indicating that antigen-independent factors, such as acute renal ischemia, are likely to be involved in the development of CAN. Hepatocyte growth factor (HGF) has been demonstrated to play a renotropic role in renal regeneration and protection from acute ischemic injury. This study was thus conducted to investigate the effect of HGF on the development of CAN, using an established rat model. HGF was administered daily (100 μg/d, intravenously) for 4 wk after engraftment. Control animals received saline solution. Allografts from control animals exhibited early evidence of severe structural collapse and necrotic cell death in the proximal tubules and outer medulla, with mononuclear cell infiltration, within 1 wk after engraftment. This was followed by sequential upregulation of adhesion molecules and cytokines, accompanied by dense macrophage infiltration. Fibrogenic events, as indicated by marked increases in transforming growth factor-β1 expression and the accumulation of smooth muscle α-actin, occurred during the same period. Control animals ultimately developed features typical of CAN, with functional deterioration and severe histologic changes; a survival rate of 50.6% by 32 wk was observed. In contrast, remarkably little early injury and no late fibrogenic events were observed for the HGF-treated group. All treated animals survived, with well preserved graft function, during the 32-wk follow-up period. These results indicate that renal protection and recovery from early allograft injury with HGF treatment greatly contribute to a reduction of susceptibility to the subsequent development of CAN in a rat model. The potential application of HGF in the prevention of CAN warrants further attention.

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Hepatocyte growth factor gene transfer improves cardiac function and remodeling via enhancing angiogenesis and bcl-2 expression and decreasing hydroxyl radicals

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2004.08.141 ◽

2004 ◽

Vol 10 (5) ◽

pp. S190

Author(s):

Chen Xuehai ◽

Minatoguchi Shinya ◽

Wang Ningyuan ◽

Lu Chuanjiang ◽

Arai Masazumi ◽

...

Keyword(s):

Growth Factor ◽

Gene Transfer ◽

Hepatocyte Growth Factor ◽

Cardiac Function ◽

Hydroxyl Radicals ◽

Factor Gene ◽

Growth Factor Gene ◽

Hepatocyte Growth

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Enhancement of retrovirus-mediated gene transfer to rat liver in vivo by infusion of hepatocyte growth factor and triiodothyronine

Journal of Hepatology ◽

10.1016/s0168-8278(00)80358-x ◽

2000 ◽

Vol 33 (2) ◽

pp. 183-188 ◽

Cited By ~ 3

Author(s):

Hisaka Minami ◽

Kouji Tada ◽

Namita Roy Chowdhury ◽

Jayanta Roy Chowdhury ◽

Morikazu Onji

Keyword(s):

Growth Factor ◽

Gene Transfer ◽

Hepatocyte Growth Factor ◽

Rat Liver ◽

Hepatocyte Growth

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The effect of gene transfer with hepatocyte growth factor for pulmonary vascular hypoplasia in neonatal porcine model

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2004.06.040 ◽

2005 ◽

Vol 129 (4) ◽

pp. 740-745 ◽

Cited By ~ 3

Author(s):

Masamichi Ono ◽

Yoshiki Sawa ◽

Yuji Miyamoto ◽

Norihide Fukushima ◽

Hajime Ichikawa ◽

...

Keyword(s):

Growth Factor ◽

Gene Transfer ◽

Hepatocyte Growth Factor ◽

Porcine Model ◽

Hepatocyte Growth

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Neonatal or hepatocyte growth factor–potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B

Blood ◽

10.1182/blood-2002-10-3050 ◽

2003 ◽

Vol 101 (10) ◽

pp. 3924-3932 ◽

Cited By ~ 73

Author(s):

Lingfei Xu ◽

Cuihua Gao ◽

Mark S. Sands ◽

Shi-Rong Cai ◽

Timothy C. Nichols ◽

...

Keyword(s):

Gene Therapy ◽

Growth Factor ◽

Gene Transfer ◽

Hepatocyte Growth Factor ◽

Retroviral Vector ◽

Factor Ix ◽

Hemophilia B ◽

Hepatocyte Growth

AbstractHemophilia B is a bleeding disorder resulting from factor IX (FIX) deficiency that might be treated with gene therapy. Neonatal delivery would correct the disease sooner than would transfer into adults, and could reduce immunological responses. Neonatal mice were injected intravenously with a Moloney murine leukemia virus–based retroviral vector (RV) expressing canine FIX (cFIX). They achieved 150% to 280% of normal cFIX antigen levels in plasma (100% is 5 μg/mL), which was functional in vitro and in vivo. Three newborn hemophilia B dogs that were injected intravenously with RV achieved 12% to 36% of normal cFIX antigen levels, which improved coagulation tests. Only one mild bleed has occurred during 14 total months of evaluation. This is the first demonstration of prolonged expression after neonatal gene therapy for hemophilia B in mice or dogs. Most animals failed to make antibodies to cFIX, demonstrating that neonatal gene transfer may induce tolerance. Although hepatocytes from newborns replicate, those from adults do not. Adult mice therefore received hepatocyte growth factor to induce hepatocyte replication prior to intravenous injection of RV. This resulted in expression of 35% of normal cFIX antigen levels for 11 months, although all mice produced anti-cFIX antibodies. This is the first demonstration that high levels of FIX activity can be achieved with an RV in adults without a partial hepatectomy to induce hepatocyte replication. We conclude that RV-mediated hepatic gene therapy is effective for treating hemophilia B in mice and dogs, although the immune system may complicate gene transfer in adults.

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