Skip to main content

Advertisement

Log in

Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Objective Therapeutic angiogenesis is a new strategy for treatment of vascular insufficiency. Hepatocyte growth factor (HGF)-induced angiogenesis has been applied to induce the neovascularization of ischemic adult tissues in preclinical studies. This report summarizes a phase I clinical trial on the safety of adenovirus-mediated human HGF (Ad-HGF) gene transfer to treat clinically significant coronary artery disease. Methods The 18 patients with severe and diffused triple vessel disease determined by coronary angiography, 1–3 of the main coronary arteries not amenable to bypassing grafting and to catheter-based revascularization were assigned to 3 study groups according to the dose of Ad-HGF (from low to high), and the total dose as follows: 5 × 109 pfu (group A, n = 6); 1 × 1010 pfu (group B, n = 6); 2 × 1010 pfu (group C, n = 6). Arterial gene transfer was performed by over-the wire balloon to the distal of the accessible artery or otherwise the ostium of the target vessels by diagnostic coronary catheter. General safety parameters and cardiac-specific parameters were measured through the preoperative period and on day 7, 21, and 35 postoperatively. The safety and tolerance of Ad-HGF for patients were evaluated according to functional and cytological assessments. Results During the acute phase up to day 35 and at 11–14 months of follow-up there were no serious adverse events. A mild fever during the first 3 days was not present at day 4, and no long term or paroxysmal fever was found. There were no acute alterations in hemodynamic parameters and the electrocardiogram remained normal. No serious pericardial effusion was reported and there were no arrhythmia on Holter registrations. Moreover, the serum levels of HGF were not changed and the serum anti-adenovirus in the patients was not detected up to day 35. Conclusions The present study demonstrates that it is feasible to safely use an adenovirus gene-transfer vector to deliver the human hepatocyte growth factor gene to individuals with clinically significant coronary artery disease by direct intracoronary injection. However, a great deal of additional work must be done before administration of Ad-HGF can be recommended for clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Rosengart TK, Patel SR, Crystal RG (1999) Therapeutic angiogenesis: protein and gene therapy delivery strategies. J Cardiovasc Res 6:29–40

    CAS  Google Scholar 

  2. Simons M, Ware JA (1996) Food for starving hearts. Nat Med 2:519–520. doi:10.1038/nm0596-519

    Article  PubMed  CAS  Google Scholar 

  3. Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G, Keshet E (1994) Upregulation of vascular endothelial growth factor expression induced by myocardial ischaemia: implications for coronary angiogenesis. Cardiovasc Res 28:1176–1179. doi:10.1093/cvr/28.8.1176

    Article  PubMed  CAS  Google Scholar 

  4. Li J, Brown LF, Hibberd MG, Grossman JD, Morgan JP, Simons M (1996) VEGF, flk–1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol 270:H1803–H1811

    PubMed  CAS  Google Scholar 

  5. Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L et al (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641. doi:10.1083/jcb.119.3.629

    Article  PubMed  CAS  Google Scholar 

  6. Jennische E, Ekberg S, Matejka GL (1993) Expression of hepatocyte growth factor in growing and regenerating rat skeletal muscle. Am J Physiol 265:C122–C128

    PubMed  CAS  Google Scholar 

  7. Ono K, Matsumori A, Shioi T, Furukawa U, Sasayama S (1997) Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model. Circulation 95:2552–2558

    PubMed  CAS  Google Scholar 

  8. Matsumoto K, Nakamura T (1996) Emerging multipotent aspects of hepatocyte growth factor. J Biochem 119:591–600

    PubMed  CAS  Google Scholar 

  9. Fliss H, Gattinger D (1996) Apoptosis in ischemic and reperfused rat myocardium. Circ Res 79:949–956

    PubMed  CAS  Google Scholar 

  10. Jayasankar V, Woo YJ, Pirolli TJ, Bish LT, Berry MF, Burdick J et al (2005) Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure. J Card Surg 20(1):93–101. doi:10.1111/j.0886-0440.2005.200373.x

    Article  PubMed  Google Scholar 

  11. Azuma J, Taniyama Y, Takeya Y, Iekushi K, Aoki M, Dosaka N et al (2006) Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy. Gene Ther 13(16):1206–1213. doi:10.1038/sj.gt.3302740

    Article  PubMed  CAS  Google Scholar 

  12. Li Y, Takemura G, Kosai K, Yuge K, Nagano S, Esaki M et al (2003) Postinfarction treatment with an adenoviral vector expressing hepatocyte growth factor relieves chronic left ventricular remodeling and dysfunction in mice. Circulation 107:2499–2506. doi:10.1161/01.CIR.0000065579.19126.B8

    Article  PubMed  CAS  Google Scholar 

  13. Ahmet I, Sawa Y, Yamaguchi T, Matsuda H (2003) Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart. Ann Thorac Surg 75(4):1283–1287. doi:10.1016/S0003-4975(02)04677-5

    Article  PubMed  Google Scholar 

  14. Aoki M, Morishita R, Taniyama Y, Kida I, Moriguchi A, Matsumoto K et al (2000) Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ETS. Gene Ther 7:417–427. doi:10.1038/sj.gt.3301104

    Article  PubMed  CAS  Google Scholar 

  15. Taniyama Y, Morishita R, Aoki M, Nakagami H, Yamamoto K, Yamazaki K et al (2001) 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 8:181–189. doi:10.1038/sj.gt.3301379

    Article  PubMed  CAS  Google Scholar 

  16. Wang W, Yang ZJ, Ma DC, Wang LS, Xu SL, Zhang YR et al (2006) Induction of collateral artery growth and improvement of post-infarct heart function by hepatocyte growth factor gene transfer. Acta Pharmacol Sin 27(5):555–560. doi:10.1111/j.1745-7254.2006.00306.x

    Article  PubMed  CAS  Google Scholar 

  17. Duan HF, Wu CT, Wu DL, Lu Y, Liu HJ, Ha XQ et al (2003) Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells overexpressing hepatocyte growth factor. Mol Ther 8(3):467–474. doi:10.1016/S1525-0016(03)00186-2

    Article  PubMed  CAS  Google Scholar 

  18. Campeau L (1976) Grading of angina pectoris. Circulation 54:522–523

    PubMed  CAS  Google Scholar 

  19. Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergman GW, Hachamovitch R, Szulc M, Kligfield PD, Okin PM, Hahn RT, Devereux RB, Post MR, Hackett NR, Foster T, Grasso TM, Lesser ML, Isom OW, Crystal RG (1999) Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100:468–474

    Google Scholar 

  20. Mukherjee D, Bhatt DL, Roe MT, Patel V, Ellis SG (1999) Direct myocardial revascularization and angiogenesis—how many patients might be eligible? Am J Cardiol 84(5):598–600. doi:10.1016/S0002-9149(99)00387-2

    Article  PubMed  CAS  Google Scholar 

  21. Yang ZJ, Ma DC, Wang W, Xu SL, Zhang YQ, Chen B et al (2006) Experimental study of bone marrow-derived mesenchymal stem cells combined with hepatocyte growth factor transplantation via noninfarct-relative artery in acute myocardial infarction. Gene Ther 13(22):1564–1568. doi:10.1038/sj.gt.3302820

    Article  PubMed  CAS  Google Scholar 

  22. Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J et al (2004) Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 44(2):203–209. doi:10.1161/01.HYP.0000136394.08900.ed

    Article  PubMed  CAS  Google Scholar 

  23. Harvey BG, Maroni J, O’Donoghue KA et al (2002) Safety of local delivery of low-and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther 13(1):15–63. doi:10.1089/10430340152712638

    Article  PubMed  CAS  Google Scholar 

  24. Worgall S, Wolff G, Falck-Pedersen E, Crystal RG (1997) Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. Hum Gene Ther 8:37–44. doi:10.1089/hum.1997.8.1-37

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This study was supported by project grants from “the key faculty of Medicine Renaissance program of Jiangsu province” and Chinese national ‘973’ and ‘863’ programs.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhi-Jian Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, ZJ., Zhang, YR., Chen, B. et al. Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease. Mol Biol Rep 36, 1323–1329 (2009). https://doi.org/10.1007/s11033-008-9315-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-008-9315-3

Keywords

Navigation