Adeno-associated virus-mediated delivery of a mutant endostatin suppresses ovarian carcinoma growth in mice

Abstract

Earlier studies have shown that a point mutation in human endostatin at position 125 (human endostatin wherein proline 125 was substituted with alanine, P125A-endostatin) improves endothelial cell binding and antiangiogenic activity. In the present study, we investigated the effect of recombinant adeno-associated virus (rAAV)-mediated gene delivery of P125A-endostatin (rAAV-P125Aendo) in a mouse model of ovarian carcinoma. Intramuscular (i.m.) injection of rAAVP125Aendo resulted in a dose-dependent increase in serum endostatin levels. Consequently, vascular endothelial growth factor-and basic fibroblast growth factor-mediated angiogenesis was significantly inhibited in mice injected with rAAV-P125Aendo as compared to control mice injected with rAAV-LacZ. Furthermore, gene therapy using rAAV-P125Aen-do construct showed sustained secretion of P125A-endostatin for up to 9 weeks after a single i.m. administration. Recombinant AAV-P125Aendo injection significantly inhibited the growth of human ovarian cancer cells in athymic nude mice. Immunofluorescence studies of residual tumors surgically removed from the rAAV-P125Aendo-treated animals showed decreased number of vessel ends and vessel length, indicating inhibition of angiogenesis. These studies suggest that recombinant AAV-mediated antiangiogenic gene therapy methods can be used to inhibit ovarian cancer growth. Gene Therapy (2005) 12, 30-38.

AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer

“…AAV9 has been shown to have enhanced tropism to muscles and neurons, high infectivity, and stable long-term expression, making it ideally suited for the treatment of tumors, where normal infected tissues (e.g., muscles) serve as a bioreactor-like source of therapeutic protein for long-term secretion into the circulation (53). To date, AAV9 has not been evaluated for the treatment of cancer, and AAVs, in general, have been underused in treating ovarian cancer, with the exceptions of AAVrh.10 delivering Bevacizumab (54) and AAV2 delivering Kringle 5 (55) or endostatin (56). The tropism of AAV9 delivered i.p., as evidenced by AAV9-GFP infecting the body wall muscle, omentum, (Fig.…”

Liposome–DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma

“…For example, use of systemic gene delivery to express endostatin or other angiogenesis inhibitors to control tumor growth has been reported previously in mouse models. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] However, potential hurdles to applying systemic gene therapy in humans include achieving efficient in vivo transfection, attaining durable in vivo gene expression, and administering the gene delivery vectors repeatedly. 2,17,23 The use of nonviral gene delivery systems, based principally on liposome-plasmid DNA-based systems, may help address some of these problems, particularly the issue of repeated gene delivery.…”

Adeno-associated virus-mediated delivery of kringle 5 of human plasminogen inhibits orthotopic growth of ovarian cancer

“…Earlier studies have shown that intramuscular administration adeno-associated virus (AAV)-based gene therapy provides long term (for 41.5 years) 26,27 and sustained delivery of angiogenesis inhibitors. 28,29 In addition, AAV-based gene therapy can transduce a broad range of host cells without evoking a strong immune response. 25,30 Using this system, we determined the effects of AAV-K5 gene therapy on ovarian cancer growth in a clinically relevant mouse model.…”