Login Register Cart 0
Research Article

Combined Analysis of Clinical Data on HGF Gene Therapy to Treat Critical Limb Ischemia in Japan

Author(s): Ryuichi Morishita*, Munehisa Shimamura, Yasushi Takeya, Hironori Nakagami, Mitsuaki Chujo, Tetsuya Ishihama, Ei Yamada and Hiromi Rakugi

Volume 20, Issue 1, 2020

Page: [25 - 35] Pages: 11

DOI: 10.2174/1566523220666200516171447

Price: $65

Abstract

Objective: The objective of this combined analysis of data from clinical trials in Japan, using naked plasmid DNA encoding hepatocyte growth factor (HGF), was to document the safety and efficacy of intramuscular HGF gene therapy in patients with critical limb ischemia (CLI).

Methods: HGF gene transfer was performed in 22 patients with CLI in a single-center open trial at Osaka University; 39 patients in a randomized, placebo-controlled, multi-center phase III trial, 10 patients with Buerger’s disease in a multi-center open trial; and 6 patients with CLI in a multi-center open trial using 2 or 3 intramuscular injections of naked HGF plasmid at 2 or 4 mg. Resting pain on a visual analogue scale (VAS) and wound healing as primary endpoints were evaluated at 12 weeks after the initial injection. Serious adverse events caused by gene transfer were detected in 7 out of 77 patients (9.09%). Only one patient experienced peripheral edema (1.30%), in contrast to those who had undergone treatment with VEGF. At 12 weeks after gene transfer, combined evaluation of VAS and ischemic ulcer size demonstrated a significant improvement in HGF gene therapy group as compared to the placebo group (P=0.020).

Results: The long-term analysis revealed a sustained decrease in the size of ischemic ulcer in HGF gene therapy group. In addition, VAS score over 50 mm at baseline (total 27 patients) demonstrated a tendency (P=0.059), but not significant enough, to improve VAS score in HGF gene therapy as compared to the placebo group.

Conclusion: The findings indicated that intramuscular injection of naked HGF plasmid tended to improve the resting pain and significantly decreased the size of the ischemic ulcer in the patients with CLI who did not have any alternative therapy, such as endovascular treatment (EVT) or bypass graft surgery. An HGF gene therapy product, CollategeneTM, was recently launched with conditional and time-limited approval in Japan to treat ischemic ulcer in patients with CLI. Further clinical trials would provide new therapeutic options for patients with CLI.

Keywords: Angiogenesis, gene therapy, critical limb ischemia, peripheral arterial disease, hepatocyte growth factor, EVT.

« Previous Next »
Graphical Abstract

[1]
Ali S, Kjeken R, Niederlaender C, et al. The European medicines agency review of Kymriah (Tisagenlecleucel) for the treatment of acute lymphoblastic leukemia and diffuse large B-Cell lymphoma. Oncologist 2019; 25(2): e321-7.
[http://dx.doi.org/10.1634/theoncologist.2019-0233] [PMID: 32043764]
[2]
Hoy SM. Onasemnogene Abeparvovec: First Global Approval. Drugs 2019; 79(11): 1255-62.
[http://dx.doi.org/10.1007/s40265-019-01162-5] [PMID: 31270752]
[3]
Sanada F, Taniyama Y, Muratsu J, et al. Gene-Therapeutic strategies targeting angiogenesis in peripheral artery disease. Medicines (Basel) 2018; 5(2): 31.
[http://dx.doi.org/10.3390/medicines5020031] [PMID: 29601487]
[4]
Suzuki J, Shimamura M, Suda H, et al. Current therapies and investigational drugs for peripheral arterial disease. Hypertens Res 2016; 39(4): 183-91.
[http://dx.doi.org/10.1038/hr.2015.134] [PMID: 26631852]
[5]
Morishita R, Nakamura S, Hayashi S, et al. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 1999; 33(6): 1379-84.
[http://dx.doi.org/10.1161/01.HYP.33.6.1379] [PMID: 10373220]
[6]
Hayashi S, Morishita R, Nakamura S, et al. Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: downregulation of HGF in response to hypoxia in vascular cells. Circulation 1999; 100(19)(Suppl.): II301-8.
[http://dx.doi.org/10.1161/01.CIR.100.suppl_2.II-301] [PMID: 10567320]
[7]
Taniyama Y, Morishita R, Aoki M, et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease. Gene Ther 2001; 8(3): 181-9.
[http://dx.doi.org/10.1038/sj.gt.3301379] [PMID: 11313789]
[8]
Taniyama Y, Morishita R, Hiraoka K, et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model: molecular mechanisms of delayed angiogenesis in diabetes. Circulation 2001; 104(19): 2344-50.
[http://dx.doi.org/10.1161/hc4401.098470] [PMID: 11696476]
[9]
Morishita R, Sakaki M, Yamamoto K, et al. Impairment of collateral formation in lipoprotein(a) transgenic mice: therapeutic angiogenesis induced by human hepatocyte growth factor gene. Circulation 2002; 105(12): 1491-6.
[http://dx.doi.org/10.1161/01.CIR.0000012146.07240.FD] [PMID: 11914260]
[10]
Nakamura Y, Morishita R, Higaki J, et al. Hepatocyte growth factor is a novel member of the endothelium-specific growth factors: additive stimulatory effect of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor. J Hypertens 1996; 14(9): 1067-72.
[http://dx.doi.org/10.1097/00004872-199609000-00004] [PMID: 8986905]
[11]
Kaga T, Kawano H, Sakaguchi M, Nakazawa T, Taniyama Y, Morishita R. Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor. Vascul Pharmacol 2012; 57(1): 3-9.
[http://dx.doi.org/10.1016/j.vph.2012.02.002] [PMID: 22361334]
[12]
Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97: 1114-23.
[http://dx.doi.org/10.1161/01.cir.97.12.1114] [PMID: 9537336]
[13]
Gorenoi V, Brehm MU, Koch A, Hagen A. Growth factors for angiogenesis in peripheral arterial disease. Cochrane Database Syst Rev2017 2017; 6(6) CD011741
[PMID: 28594443]
[14]
MHLW Panel OKs AnGes’ gene therapy collategene for conditional approval. Available from https://pj.jiho.jp/article/239483
[15]
Shigematsu H, Yasuda K, Iwai T, et al. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther 2010; 17(9): 1152-61.
[http://dx.doi.org/10.1038/gt.2010.51] [PMID: 20393508]
[16]
Shigematsu H, Yasuda K, Sasajima T, et al. Transfection of human HGF plasmid DNA improves limb salvage in Buerger’s disease patients with critical limb ischemia. Int Angiol 2011; 30(2): 140-9.
[PMID: 21427651]
[17]
Morishita R, Aoki M, Hashiya N, et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 2004; 44(2): 203-9.
[http://dx.doi.org/10.1161/01.HYP.0000136394.08900.ed] [PMID: 15238569]
[18]
Morishita R, Makino H, Aoki M, et al. Phase I/IIa clinical trial of therapeutic angiogenesis using hepatocyte growth factor gene transfer to treat critical limb ischemia. Arterioscler Thromb Vasc Biol 2011; 31(3): 713-20.
[http://dx.doi.org/10.1161/ATVBAHA.110.219550] [PMID: 21183732]
[19]
Makino H, Aoki M, Hashiya N, et al. Long-term follow-up evaluation of results from clinical trial using hepatocyte growth factor gene to treat severe peripheral arterial disease. Arterioscler Thromb Vasc Biol 2012; 32(10): 2503-9.
[http://dx.doi.org/10.1161/ATVBAHA.111.244632] [PMID: 22904270]
[20]
Suda H, Murakami A, Kaga T, Tomioka H, Morishita R. Beperminogene perplasmid for the treatment of critical limb ischemia. Expert Rev Cardiovasc Ther 2014; 12(10): 1145-56.
[http://dx.doi.org/10.1586/14779072.2014.955850] [PMID: 25190335]
[21]
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013; 48(3): 452-8.
[http://dx.doi.org/10.1038/bmt.2012.244] [PMID: 23208313]
[22]
Nikol S, Baumgartner I, Van Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 2008; 16: 972-8.
[http://dx.doi.org/10.1038/mt.2008.33]
[23]
Gu Y, Zhang J, Guo L, et al. A phase I clinical study of naked DNA expressing two isoforms of hepatocyte growth factor to treat patients with critical limb ischemia. J Gene Med 2011; 13(11): 602-10.
[http://dx.doi.org/10.1002/jgm.1614] [PMID: 22015632]
[24]
De Haro J, Acin F, Lopez-Quintana A, Florez A, Martinez-Aguilar E, Varela C. Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 2009; 24(5): 321-8.
[http://dx.doi.org/10.1007/s00380-008-1140-z] [PMID: 19784813]
[25]
Barć P, Antkiewicz M, Śliwa B, Baczyńska D, Witkiewicz W, Skóra JP. Treatment of critical limb ischemia by pIRES/VEGF165/HGF administration. Ann Vasc Surg 2019; 60: 346-54.
[http://dx.doi.org/10.1016/j.avsg.2019.03.013] [PMID: 31200059]
[26]
Gu Y, Cui S, Wang Q, et al. A randomized, double-blind, placebo-controlled phase II study of hepatocyte growth factor in the treatment of critical limb ischemia. Mol Ther 2019; 27: 2158-65.
[http://dx.doi.org/10.1016/j.ymthe.2019.10.017] [PMID: 31805256]
[27]
Kato N, Nemoto K, Nakanishi K, et al. Nonviral gene transfer of human hepatocyte growth factor improves streptozotocin-induced diabetic neuropathy in rats. Diabetes 2005; 54(3): 846-54.
[http://dx.doi.org/10.2337/diabetes.54.3.846] [PMID: 15734864]
[28]
Ajroud-Driss S, Christiansen M, Allen JA, Kessler JA. Phase 1/2 open-label dose-escalation study of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with painful diabetic peripheral neuropathy. Mol Ther 2013; 21(6): 1279-86.
[http://dx.doi.org/10.1038/mt.2013.69] [PMID: 23609019]
[29]
Kessler JA, Smith AG, Cha BS, et al. Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy. Ann Clin Transl Neurol 2015; 2(5): 465-78.
[http://dx.doi.org/10.1002/acn3.186] [PMID: 26000320]

Rights & Permissions Print Cite
Article Metrics
37
© 2024 Bentham Science Publishers | Privacy Policy