Gene therapy for myocardial angiogenesis

Losordo, Douglas W.; Vale, Peter R.; Isner, Jeffrey M.

doi:10.1016/s0002-8703(99)70333-9

Cited by 92 publications

(52 citation statements)

References 36 publications

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“…These angiogenic effects are considered different studies (31). The aim of our study was to evaluate the safety and among investigators to be very important when cell therapy is considered an option for human patients (19).…”

Section: Introductionmentioning

confidence: 99%

“…efficacy of a proprietarily designed protocol, the CellPraxis Refractory Angina Cell Therapy Protocol (ReAngiogenic effects were reported in several preclinical studies (6,19). Mobilization of mouse bone marrow ACT), in which a single series of multiple intramyocardial injections of a specific BMMC formulation is (BM) cells (25) or sheep cord blood mononuclear cells (42) into the circulation after acute myocardial infarction performed as the sole surgical therapy for these patients.…”

Section: Introductionmentioning

confidence: 99%

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Refractory Angina Cell Therapy (ReACT) Involving Autologous Bone Marrow Cells in Patients without Left Ventricular Dysfunction: A Possible Role for Monocytes

Hossne

Invitti²,

Buffolo

et al. 2009

Cell Transplant

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Autologous bone marrow mononuclear cell (BMMC) transplantation has emerged as a potential therapeutic option for refractory angina patients. Previous studies have shown conflicting myocardium reperfusion results. The present study evaluated safety and efficacy of CellPraxis Refractory Angina Cell Therapy Protocol (ReACT), in which a specific BMMC formulation was administered as the sole therapy for these patients. The phase I/IIa noncontrolled, open label, clinical trial, involved eight patients with refractory angina and viable ischemic myocardium, without left ventricular dysfunction and who were not suitable for conventional myocardial revascularization. ReACT is a surgical procedure involving a single series of multiple injections (40-90 injections, 0.2 ml each) into ischemic areas of the left ventricle. Primary endpoints were Canadian Cardiovascular Society Angina Classification (CCSAC) improvement at 18 months follow-up and myocardium ischemic area reduction (assessed by scintigraphic analysis) at 12 months follow-up, in correlation with a specific BMMC formulation. Almost all patients presented progressive improvement in angina classification beginning 3 months (p = 0.008) postprocedure, which was sustained at 18 months follow-up (p = 0.004), as well as objective myocardium ischemic area reduction at 12 months (decrease of 84.4%, p < 0.004). A positive correlation was found between monocyte concentration and CCSAC improvement (r = −0.759, p < 0.05). Improvement in CCSAC, followed by correlated reduction in scintigraphic myocardium ischemic area, strongly suggests neoangiogenesis as the main stem cell action mechanism. The significant correlation between number of monocytes and improvement strongly supports a cell-related effect of Re-ACT. ReACT appeared safe and effective.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Refractory Angina Cell Therapy (ReACT) Involving Autologous Bone Marrow Cells in Patients without Left Ventricular Dysfunction: A Possible Role for Monocytes

Hossne

Invitti²,

Buffolo

et al. 2009

Cell Transplant

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“…These properties explain the large number of preclinical and clinical gene transfer studies to muscle with both viral and nonviral vectors (14,15).…”

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confidence: 99%

An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus

Maione

Rocca

Giannetti

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Helper-dependent adenoviral vectors deleted of all viral coding sequences have shown an excellent gene expression profile in a variety of animal models, as well as a reduced toxicity after systemic delivery. What is still unclear is whether long-term expression and therapeutic dosages of these vectors can be obtained also in the presence of a preexisting immunity to adenovirus, a condition found in a high proportion of the adult human population. In this study we performed intramuscular delivery of helper-dependent vectors carrying mouse erythropoietin as a marker transgene. We found that low doses of helper-dependent adenoviral vectors can direct long-lasting gene expression in the muscles of fully immunocompetent mice. The best performance-i.e., 100% of treated animals showing sustained expression after 4 months-was achieved with the latest generation helper-dependent backbones, which replicate and package at high efficiency during vector propagation. Moreover, efficient and prolonged transgene expression after intramuscular injection was observed with limited vector load also in animals previously immunized against the same adenovirus serotype. These data suggest that human gene therapy by intramuscular delivery of helper-dependent adenoviral vectors is feasible. R eplication-deficient adenoviral (Ad) vectors deleted of one or more early genes (first-and second-generation Ad vectors) are among the most efficient vehicles for in vivo gene delivery, but their utilization for therapeutic purposes is limited by the transient nature of transgene expression and the systemic toxicity, which are both due to inflammatory and immune responses triggered by the residual expression of viral proteins (1-5). The development of Ad vectors deleted of all viral coding sequences offers the prospect of a safer and more efficient way to deliver genes (6). Production of fully deleted Ad vectors, also called helper-dependent (HD) Ad vectors, is possible thanks to the supply in trans of the viral proteins required for replication and packaging by a helper first-generation virus (7).Previous studies by several laboratories have shown improved performances of HD vs. first-generation vectors after intravenous (i.v.) injection as to efficacy of transduction, longevity of transgene expression, and systemic toxicity (8-11). These studies strongly suggested that latest generation adenoviruses may be useful for human applications. However, delivery of Ad vectors (including HD vectors) to human recipients may be rendered particularly difficult when a preexisting immunity against an adenovirus serotype identical to, or cross-reactive with, the one used for gene transfer has previously developed as a consequence of a natural infection. This interfering effect is expected to be particularly pronounced in the case of i.v. delivery, because transducing vector particles will be exposed to circulating neutralizing antibodies before reaching the main target organ, the liver. It is therefore important to evaluate performance, therapeutic efficacy, an...

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“…The objective demonstration of an improvement in perfusion is fundamental when dealing with techniques of angiogenesis, which, according to data in the literature, are highly susceptible to the placebo effect [13][14][15][16][17][18][19] . Recently, improvement in the symptoms of patients undergoing transmyocardial laser revascularization have been reported [7][8][9][10][11][12] ; those data, however, could not be confirmed in randomized, double-blind studies 56,57 .…”

Section: Discussionmentioning

confidence: 99%

“…Those strategies comprise the following: intermittent or long-term use of urokinase [3][4][5] ; neurostimulation 6 ; transmyocardial revascularization by use of laser or radiofrequency, or mechanical transmyocardial revascularization [7][8][9][10][11][12] ; and neoangiogenesis through implantation of endothelial growth factors [13][14][15][16][17][18][19][20] . However, none of those techniques, despite some years of development, has proved to be effective in changing the poor prognosis of those patients to justify its routine clinical use [7][8][9][10][11][12] .…”

mentioning

confidence: 99%

Melhora sintomática e da capacidade de exercício após o transplante autólogo, transendocárdico, de células mononucleares da medula óssea em pacientes com cardiopatia isquêmica grave, sustentada até o sexto mês de evolução

Dohmann

Perin

Borojević

et al. 2005

Arq. Bras. Cardiol.

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Gene therapy for myocardial angiogenesis

Cited by 92 publications

References 36 publications

Refractory Angina Cell Therapy (ReACT) Involving Autologous Bone Marrow Cells in Patients without Left Ventricular Dysfunction: A Possible Role for Monocytes

Refractory Angina Cell Therapy (ReACT) Involving Autologous Bone Marrow Cells in Patients without Left Ventricular Dysfunction: A Possible Role for Monocytes

An improved helper-dependent adenoviral vector allows persistent gene expression after intramuscular delivery and overcomes preexisting immunity to adenovirus

Melhora sintomática e da capacidade de exercício após o transplante autólogo, transendocárdico, de células mononucleares da medula óssea em pacientes com cardiopatia isquêmica grave, sustentada até o sexto mês de evolução

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