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

Objectives: 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. Conclusions: 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.

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Progress of Gene Therapy in Cardiovascular Disease

Hypertension ◽

10.1161/hypertensionaha.120.14478 ◽

2020 ◽

Vol 76 (4) ◽

pp. 1038-1044

Author(s):

Munehisa Shimamura ◽

Hironori Nakagami ◽

Fumihiro Sanada ◽

Ryuichi Morishita

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Dna Vaccine ◽

Critical Limb Ischemia ◽

Dna Vaccines ◽

Limb Ischemia ◽

Hepatocyte Growth

Gene therapy has been extensively studied in peripheral and cardiac ischemia, heart and vein graft failure, and dyslipidemia, but most clinical trials failed to show their efficacies despite good outcomes in preclinical studies. So far, 2 gene therapies for dyslipidemia and one for critical limb ischemia in peripheral artery disease have been approved. In critical limb ischemia, gene therapy using proangiogenic factors has emerged as a novel therapeutic modality for promoting angiogenesis. Initial researches mainly focused on vascular endothelial growth factor, fibroblast growth factor, or hepatocyte growth factor. After the favorable results of basic research, several phase I and II clinical trials of these proangiogenic factors have shown promising results. However, only a phase III clinical trial of the intramuscular injection of hepatocyte growth factor plasmid DNA has shown successful outcomes, and it was recently approved in Japan for treating patients with critical limb ischemia who have ulcers and for whom no alternative therapeutic options are available. DNA vaccine is another promising modality of gene therapy. An antitumor vaccine suppressing angiogenesis through the inhibition of proangiogenic factors and an antihypertensive vaccine inhibiting the renin–angiotensin system are representative DNA vaccines. The advantage of DNA vaccine is its long-term effectiveness with a few vaccinations; however, the benefits and risks, such as adverse T-cell reaction against self-antigen or long-term side effects, of DNA vaccines should be carefully evaluated. In this review, we discuss the recent advances in proangiogenic gene therapy for critical limb ischemia and DNA vaccine for hypertension.

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1082. Recombinant Sendai Virus-Mediated Gene Therapy for Experimental Critical Limb Ischemia: FGF-2 Gene Transfer Can Stimulate Endogenous HGF Expression, Regardless to Hypoxia-Mediated down Regulation in Ischemic Limbs

Molecular Therapy ◽

10.1016/s1525-0016(16)43912-2 ◽

2002 ◽

Vol 5 (5) ◽

pp. S351

Keyword(s):

Gene Therapy ◽

Gene Transfer ◽

Critical Limb Ischemia ◽

Sendai Virus ◽

Limb Ischemia ◽

Down Regulation

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Update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia

Journal of Vascular Surgery ◽

10.1016/j.jvs.2012.03.255 ◽

2012 ◽

Vol 56 (1) ◽

pp. 264-266 ◽

Cited By ~ 36

Author(s):

Richard J. Powell

Keyword(s):

Clinical Trials ◽

Critical Limb Ischemia ◽

Biologic Therapy ◽

Limb Ischemia

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A free radical scavenger but not FGF-2-mediated angiogenic therapy rescues myonephropathic metabolic syndrome in severe hindlimb ischemia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01006.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. H1484-H1492 ◽

Cited By ~ 6

Author(s):

Kazuhiro Kaneko ◽

Yoshikazu Yonemitsu ◽

Takaaki Fujii ◽

Mitsuho Onimaru ◽

Chen-Hao Jin ◽

...

Keyword(s):

Metabolic Syndrome ◽

Gene Transfer ◽

Critical Limb Ischemia ◽

Sendai Virus ◽

Radical Scavenging ◽

Limb Ischemia ◽

Free Radical Scavenger ◽

Intercellular Adhesion Molecule ◽

Radical Scavenger ◽

Intercellular Adhesion Molecule 1

The therapeutic use of angiogenic factors shows promise in the treatment of critical limb ischemia; however, its potential for myonephropathic metabolic syndrome (MNMS), a fatal complication caused by arterial reconstruction, has not been elucidated. The objective of this study was to evaluate the effectiveness of recombinant Sendai virus-mediated gene transfer of fibroblast growth factor-2 (FGF-2) directly compared with that of a radical scavenger, MCI-186, in a rat model of MNMS. MNMS was surgically induced by aortic occlusion below renal arteries for 4 h, followed by 6 h of reperfusion. Administration of MCI-186 (twice; iv 5 min before induced ischemia and ip 5 min before reperfusion; 10 mg/kg, respectively), but not FGF-2 gene transfer (once, 48 h before induced ischemia), dramatically prevented the increase of serum biochemical markers as well as the edema of the gastrocnemius muscle. The effect of MCI-186 was accompanied by the marked suppression of the neutrophilic infiltration into the local (muscle) and remote (lung) organs. Although serum and muscular levels of a neutrophil-chemoattractant (growth-related oncogene/cytokine-induced neutrophil chemoattractant-1) were not affected by any treatment, the serum level of soluble intercellular adhesion molecule-1 was decreased by treatment with MCI-186 but not by treatment with FGF-2. These results suggest the distinct mechanism of MNMS from critical limb ischemia without reperfusion. Therefore, radical scavenging should be paid more attention than therapeutic angiogenesis when arterial circulation is reconstructed.

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Constitutive Expression of phVEGF 165 After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia

Circulation ◽

10.1161/circ.99.22.2967/b ◽

1999 ◽

Vol 99 (22) ◽

Cited By ~ 2

Author(s):

Anne Arveschoug ◽

Knud S. Christensen

Keyword(s):

Gene Transfer ◽

Critical Limb Ischemia ◽

Constitutive Expression ◽

Limb Ischemia ◽

Collateral Vessel ◽

Vessel Development

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Functional prognosis of critical limb ischemia and efficacy of restoration of direct flow below the ankle

Vascular ◽

10.1177/1708538118798886 ◽

2018 ◽

Vol 27 (1) ◽

pp. 38-45

Author(s):

Tadashi Furuyama ◽

Toshihiro Onohara ◽

Ryosuke Yoshiga ◽

Keiji Yoshiya ◽

Yutaka Matsubara ◽

...

Keyword(s):

Endovascular Therapy ◽

Critical Limb Ischemia ◽

Ulcer Healing ◽

Therapy Group ◽

Limb Ischemia ◽

Direct Flow ◽

Free Survival ◽

Ambulatory Status ◽

Bypass Group ◽

One Year

Objective Patients with critical limb ischemia have serious systemic comorbidities and are at high risk of impairment of limb function. In this study, we assessed the prognostic factors of limbs after revascularization. Methods In this retrospective single-center cohort study, from April 2008 to December 2012, we treated 154 limbs of 121 patients with critical limb ischemia by the endovascular therapy-first approach based on the patients’ characteristics. The primary end point was amputation-free survival. Secondary end points were patency of a revascularized artery, major adverse limb events, or death. Furthermore, we investigated the ambulatory status one year after revascularization as prognosis of limb function. Results Endovascular therapy was performed in 85 limbs in 65 patients as the initial therapy (endovascular therapy group) and surgical reconstructive procedures (bypass group) were performed in 69 limbs in 56 patients. Early mortality within 30 days was not observed in either group. The primary patency rate was significantly better in the bypass group than in the endovascular therapy group ( p < 0.0001). Furthermore, the secondary patency rate was similar between the two groups ( p = 0.0096). There were no significant differences in amputation-free survival and major adverse limb event between the two groups. Univariate analysis showed that ulcer healing ( p < 0.0001), no hypoalbuminemia ( p = 0.0019), restoration of direct flow below the ankle ( p = 0.0219), no previous cerebrovascular disease ( p = 0.0389), and Rutherford 4 ( p = 0.0469) were predictive factors for preservation of ambulatory status one year after revascularization. In multivariate analysis, ulcer healing ( p < 0.0001) and restoration of direct flow below the ankle ( p = 0.0060) were significant predictors. Conclusions Ulcer healing and restoration of direct flow below the ankle are independently associated with prognosis of limb functions in patients who undergo infrainguinal arterial reconstruction.

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Gene therapy for critical limb ischemia: Per aspera ad astra

Current Gene Therapy ◽

10.2174/1566523221666210712185742 ◽

2021 ◽

Vol 21 ◽

Author(s):

Vyacheslav Z. Tarantul ◽

Alexander V. Gavrilenko

Keyword(s):

Gene Therapy ◽

Critical Limb Ischemia ◽

Viral Vectors ◽

Ex Vivo ◽

Single Gene ◽

Public Health Problem ◽

Limb Ischemia ◽

Therapeutic Angiogenesis ◽

Effective Treatment Option

: Peripheral artery diseases remain a serious public health problem. Although there are many traditional methods for their treatment using conservative therapeutic techniques and surgery, gene therapy is an alternative and potentially more effective treatment option especially for “no option” patients. This review treats the results of many years of research and application of gene therapy as an example of treatment of patients with critical limb ischemia. Data on successful and unsuccessful attempts to use this technology for treating this disease are presented. Trends in changing the paradigm of approaches to therapeutic angiogenesis are noted: from viral vectors to non-viral vectors, from gene transfer to the whole organism to targeted transfer to cells and tissues, from single gene use to combination of genes; from DNA therapy to RNA therapy, from in vivo therapy to ex vivo therapy.

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