Abstract
Great potential for limb salvaging with basic fibroblast growth factor (FGF-2) expressed from a Sendai virus vector with the full-length viral genome (SeV/FGF-2) in the target muscle was demonstrated in animal models of severe limb ischemia. The exogenously expressed FGF-2 induced other endogenous angiogenic factors, including vascular endothelial growth factor and hepatocyte growth factor in a highly concerted fashion, and this was shown to underlie the remarkable limb salvaging. These results led to the initiation of a phase I/IIa clinical trial for peripheral arterial disease (PAD) of humans. To be better prepared for unforeseen adverse events, this clinical trial used the F gene-deleted, nontransmissible, and hence safer (than SeV/FGF-2) version that carried the human FGF-2 gene (∆FSeV/FGF-2; product code, DVC1-0101). Overall, DVC1-0101 appeared to be safe, giving rise to no serious adverse events in various criteria. Moreover, it exerted a significant therapeutic effect from a number of clinical aspects. DVC1-0101 represents the first case of the potential diverse medical applications of SeV vector. It is now hoped to move on to an advanced phase of clinical trial with a larger number of patients and placebo group to firmly establish the safety and efficacy of DVC1-0101.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Comerota AJ, Throm RC, Miller K, Henry T, Chronos N, Laird J, Sequeira R, Kent CK, Bacchetta M, Goldman C, Salenius JP, Schmieder FA, Pilsudski R (2002) Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg 35:930–936
Fujii T, Yonemitsu Y, Onimaru M, Tanii M, Nakano T, Egashira K, Takehara T, Inoue M, Hasegawa M, Kuwano H, Sueishi K (2006) Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: critical role of the inflammatory/arteriogenic pathway. Arterioscler Thromb Vasc Biol 226:2483–2489
Ikeda Y, Yonemitsu Y, Sakamoto T, Ishibashi T, Ueno H, Kato A, Nagai Y, Fukumura M, Inomata H, Hasegawa M, Sueishi K (2002) Recombinant Sendai virus-mediated gene transfer into adult rat retinal tissue: efficient gene transfer by brief exposure. Exp Eye Res 75:39–48
Kubo H, Cao R, Brakenhielm E, Mäkinen T, Cao Y, Alitalo K (2002) Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 99:8868–8873
Lazarous DF, Unger EF, Epstein SE, Stine A, Arevalo JL, Chew EY, Quyyumi AA (2000) Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial. J Am Coll Cardiol 36:1239–1244
Lederman RJ, Mendelsohn FO, Anderson RD, Saucedo JF, Tenaglia AN, Hermiller JB, Hillegass WB, Rocha-Singh K, Moon TE, Whitehouse MJ, Annex BH, TRAFFIC Investigators (2002) Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 35:2053–2058
Masaki I, Yonemitsu Y, Yamashita A, Sata S, Tanii M, Komori K, Nakagawa K, Hou X, Nagai Y, Hasegawa M, Sugimachi K, Sueishi K (2002) Angiogenic gene therapy for experimental critical limb ischemia: acceleration of limb loss by overexpression of VEGF165 but not of FGF-2. Circ Res 90:966–973
Onimaru M, Yonemitsu Y, Tanii M, Nakagawa K, Masaki I, Okano S, Ishibashi H, Shirasuna K, Hasegawa M, Sueishi K (2002) FGF-2 gene transfer can stimulate HGF irrespective of hypoxia-mediated downregulation in ischemic limbs. Circ Res 91:923–930
Onimaru M, Yonemitsu Y, Fujii T, Tanii M, Nakano T, Nakagawa K et al (2009) VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. Am J Physiol Heart Circ Physiol 297:H1685–H1696
Rajagopalan S, Mohler ER III, Lederman RJ, Mendelsohn FO, Saucedo JF, Goldman CK, Blebea J, Macko J, Kessler PD, Rasmussen HS, Annex BH (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 108:1933–1938
Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN (1997) Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 26:517–538
Shoji T, Yonemitsu Y, Komori K, Tanii M, Itoh H, Sata S, Shimokawa H, Hasegawa M, Sueishi K, Maehara Y (2003) Intramuscular gene transfer of FGF-2 attenuates regenerative endothelial dysfunction and inhibits neointimal hyperplasia of autologous femoral vein grafts in poor runoff limbs of rabbit. Am J Physiol Heart Circ Physiol 285:H173–H182
Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM (1994) Therapeutic angiogenesis: a single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 93:662–670
Tsutsumi N, Yonemitsu Y, Shikada Y, Onimaru M, Tanii M, Okano S, Kaneko K, Hasegawa M, Hashizume M, Maehara Y, Sueishi K (2004) Essential role of PDGFRα-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo: role of PDGFRα during angiogenesis. Circ Res 94:1186–1194
Weitz JI, Byrne J, Clagett GP, Farkouh ME, Porter JM, Sackett DL, Strandness DE Jr, Taylor LM (1996) Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation 94:3026–3049
Yonemitsu Y, Kitson C, Ferrari S, Farley R, Griesenbach U, Judd D, Steel R, Scheid P, Zhu J, Jeffery PK, Kato A, Hasan MK, Nagai Y, Masaki I, Fukumura M, Hasegawa M, Geddes DM, Alton EW (2000) Efficient gene transfer to airway epithelium using recombinant Sendai virus. Nat Biotechnol 18:970–973
Yonemitsu Y, Matsumoto T, Itoh H, Okazaki J, Uchiyama M, Yoshida K, Onimaru M, Onohara T, Inoguchi H, Kyuragi R, Shimokawa M, Ban H, Tanaka M, Inoue M, Shu T, Hasegawa M, Nakanishi Y, Maehara Y (2013) DVC1-0101 to treat peripheral arterial disease: a phase I/IIa open-label dose-escalation clinical trial. Mol Ther 21:707–714
Acknowledgments
The authors thank Professor Yoichi Nakanishi, Mss. Keiko Kikutake, Michi Onizuka, and Nozomi Kataoka for their clinical research coordination, Ms. Akiko Kanaya for her help with drug preservation, Ms. Mio Yoneda-Maehara for her help with the trial paperwork, and Ms. Rio Yamauchi, Mr. Takeshi Maruoka, and Minoru Ido at EPS Co. for their help with the trial management. This study was supported in part by a Grant for Translational Research from MHLW to Y.Y.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Japan
About this chapter
Cite this chapter
Yonemitsu, Y., Matsumoto, T., Maehara, Y. (2013). Gene Therapy for Peripheral Arterial Disease Using Sendai Virus Vector: From Preclinical Studies to the Phase I/IIa Clinical Trial. In: Nagai, Y. (eds) Sendai Virus Vector. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54556-9_8
Download citation
DOI: https://doi.org/10.1007/978-4-431-54556-9_8
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-54555-2
Online ISBN: 978-4-431-54556-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)