Jornal Vascular Brasileiro
Jornal Vascular Brasileiro
Review Article

Terapia gênica de isquemia de membro é uma realidade?

Is gene therapy for limb ischemia a reality?

Sang Won Han; Carlos Alberto Vergani Junior; Paulo Eduardo Ocke Reis

Downloads: 3
Views: 244


Resumo: O conceito de terapia angiogênica surgiu no início da década de 90, o que pode ser feito com genes que codificam fatores de crescimento para promover a formação de novos vasos e o remodelamento de vasos colaterais. Como o procedimento dessa terapia geralmente consiste em apenas injeções locais de vetores, esse processo é pouco invasivo, rápido e de simples realização. Entretanto, desde as primeiras evidências clínicas do efeito de terapia gênica com o fator de crescimento de endotélio vascular (vascular endothelial growth factor, VEGF) vistos nos pacientes com doença arterial obstrutiva periférica até hoje, apenas dois fármacos de terapia angiogênica foram aprovados, um na Rússia e outro no Japão, o que parece um número muito pequeno diante do grande número de investimentos feitos por meio de estudos pré-clínicos e clínicos. Afinal, podemos considerar que a terapia angiogênica já é uma realidade?


terapia gênica, aterosclerose, doença arterial periférica, isquemia de membro


The concept of angiogenic therapy emerged in the early 1990s. The method employs genes that encode growth
factors to promote formation of new vessels and remodeling of collateral vessels. Since the procedure involved in
this therapy usually only consists of local injections of vectors, the process is minimally invasive, quick, and simple
to perform. However, since the first clinical evidence of the effects of gene therapy with vascular endothelial growth
factor (VEGF) was observed in patients with peripheral artery disease, to date only two angiogenic therapy drugs
have been approved, one in Russia and another in Japan, which seem a very small number, in view of the large volume
of investment made in pre-clinical and clinical studies. After all, can we conclude that angiogenic therapy is a reality? 


gene therapy; atherosclerosis; peripheral artery disease; limb ischemia.


1 Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;2013(382):1329-40. PMid:23915883.

2 Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45(1 Suppl):S5-67.

3 Stoyioglou A, Jaff MR. Medical treatment of peripheral arterial disease: a comprehensive review. J Vasc Interv Radiol. 2004;2004(15):1197-207. PMid:15525738.

4 Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;1992(326):381-6. PMid:1729621.

5 McCann AB, Jaff MR. Treatment strategies for peripheral artery disease. Expert Opin Pharmacother. 2009;2009(10):1571-86. PMid:19527186.

6 Hirsch AT, Hartman L, Town RJ, Virnig BA. National health care costs of peripheral arterial disease in the Medicare population. Vasc Med. 2008;13(3):209-15. PMid:18687757.

7 Isner JM. Therapeutic angiogenesis: a new frontier for vascular therapy. Vasc Med. 1996;1(1):79-87. PMid:9546920.

8 Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;1972(175):949-55. PMid:5061866.

9 Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;1995(270):475-80. PMid:7570001.

10 Abedia. [site on the Internet]. United Kingdom: John Wiley and Sons Ltd.; 2019. [cited 2019 may 22].

11 Schirmbeck R, Reimann J, Kochanek S, Kreppel F. The immunogenicity of adenovirus vectors limits the multispecificity of CD8 T-cell responses to vector-encoded transgenic antigens. Mol Ther. 2008;2008(16):1609-16. PMid:18612271.

12 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6(4):389-95. PMid:10742145.

13 Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669-76. PMid:12778165.

14 Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235-53. PMid:19247306.

15 Morishita R, Aoki M, Hashiya N, et al. Therapeutic angiogenesis using hepatocyte growth factor (HGF). Curr Gene Ther. 2004;4(2):199-206. PMid:15180586.

16 Creager MA, Olin JW, Belch JJ, et al. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation. 2011;2011(124):1765-73. PMid:21947297.

17 Rajagopalan S, Olin J, Deitcher S, et al. Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience. Circulation. 2007;2007(115):1234-43. PMid:17309918.

18 Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2012;2011(2):1117-33. PMid:22866203.

19 Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;1989(58):575-606. PMid:2549857.

20 Cao R, Brakenhielm E, Pawliuk R, et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med. 2003;2003(9):604-13. PMid:12669032.

21 Baumgartner I, Chronos N, Comerota A, et al. Local gene transfer and expression following intramuscular administration of FGF-1 plasmid DNA in patients with critical limb ischemia. Mol Ther. 2009;17(5):914-21. PMid:19240689.

22 Comerota AJ, Throm RC, Miller KA, et al. 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. 2002;2002(35):930-6. PMid:12021709.

23 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(5):972-8.

24 Belch J, Hiatt WR, Baumgartner I, et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet. 2011;2011(377):1929-37. PMid:21621834.

25 Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad, Ser B, Phys Biol Sci. 2010;2010(86):588-610. PMid:20551596.

26 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;2012(57):3-9. PMid:22361334.

27 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. 2010;2011(31):713-20. PMid:21183732.

28 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;2010(17):1152-61. PMid:20393508.

29 Henry TD, Hirsch AT, Goldman J, et al. Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study. Gene Ther. 2011;2011(18):788-94. PMid:21430785.

30 Hartikainen J, Hassinen I, Hedman A, et al. Adenoviral intramyocardial VEGF-DDeltaNDeltaC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J. 2017;2017(38):2547-55. PMid:28903476.

31 Rissanen TT, Markkanen JE, Gruchala M, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003;2003(92):1098-106. PMid:12714562.

32 Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life. 2009;2009(61):915-22. PMid:19658168.

33 Isner JM, Walsh K, Symes J, et al. Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease. Hum Gene Ther. 1996;1996(7):959-88. PMid:8727509.

34 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;1998(97):1114-23. PMid:9537336.

35 Kusumanto YH, van Weel V, Mulder NH, et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum Gene Ther. 2006;2006(17):683-91. PMid:16776576.

36 Rajagopalan S, Mohler ER 3rd, Lederman RJ, et al. 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. 2003;2003(108):1933-8. PMid:14504183.

37 Deev RV, Bozo IY, Mzhavanadze ND, et al. pCMV-vegf165 intramuscular gene transfer is an effective method of treatment for patients with chronic lower limb ischemia. J Cardiovasc Pharmacol Ther. 2015;2015(20):473-82. PMid:25770117.

38 Martins L, Martin PK, Han SW. Angiogenic properties of mesenchymal stem cells in a mouse model of limb ischemia. Methods Mol Biol. 2014;1213:147-69. PMid:25173381.

39 Dokun AO, Keum S, Hazarika S, et al. A quantitative trait locus (LSq-1) on mouse chromosome 7 is linked to the absence of tissue loss after surgical hindlimb ischemia. Circulation. 2008;117(9):1207-15. PMid:18285563.

40 del Solar G, Giraldo R, Ruiz-Echevarria MJ, Espinosa M, Díaz-Orejas R. Replication and control of circular bacterial plasmids. Microbiol Mol Biol Rev. 1998;62(2):434-64. PMid:9618448.

41 Yoshida WB. Angiogenesis, arteriogenesis and vasculogenesis: treatment of the future for lower limb critical ischemia? J Vasc Bras. 2005;4(4):316-8.

42 Kim Y, Kim H, Cho H, Bae Y, Suh K, Jung J. Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell Physiol Biochem. 2007;20(6):867-76. PMid:17982269.

43 Cunha FF, Martins L, Martin PKM, Stilhano RS, Paredes Gamero EJ, Han SW. Comparison of treatments of peripheral arterial disease with mesenchymal stromal cells and mesenchymal stromal cells modified with granulocyte and macrophage colony-stimulating factor. Cytotherapy. 2013;15(7):820-9. PMid:23660332.

44 Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229(2):176-85. PMid:23096265.

45 Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677-86. PMid:15530839.

46 Sacramento CB, Cantagalli VD, Grings M, et al. Granulocyte-macrophage colony-stimulating factor gene based therapy for acute limb ischemia in a mouse model. J Gene Med. 2009;11(4):345-53. PMid:19194978.

47 Sacramento CB, Silva FH, Nardi NB, et al. Synergistic effect of vascular endothelial growth factor and granulocyte colony-stimulating factor double gene therapy in mouse limb ischemia. J Gene Med. 2010;12(3):310-9. PMid:20077434.

48 Agência Nacional de Vigilância Sanitária – ANVISA. Terapias avançadas. Brasília: ANVISA; 2019. [cited 2019 may 22].

5ecfc4240e88253a24e6aafa jvb Articles

J Vasc Bras

Share this page
Page Sections