Terapia gênica para cardiopatia isquêmica: revisão de ensaios clínicos Gene therapy for ischemic heart disease: review of clinical trials (original) (raw)
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1. Master’s Degree of the Postgraduation Program of the Cardiology Institute of Rio Grande do Sul/University Foundation of Cardiology (IC/FUC), Porto Alegre, RS, Brazil. 2. PhD Student of the Postgraduation Program of IC/FUC, Porto Alegre, RS, Brazil. 3. Cardiac Sur geon of IC/FUC, Porto Alegre, RS, Brazil. 4. Cardiologist of IC/FUC, Porto Alegre, RS, Brazil. 5. Biologist and Collaborator Researcher of IC/FUC, Porto Alegre, RS, Brazil. 6. PhD; Institute of Cardiology of Rio Grande do Sul/University Foundation of Cardiology (IC/FUC) and Federal University of Health Sciences of Porto Alegre (UFSCPA), Porto Alegre, RS, Brazil. Bruna Eibel , Clarissa G. Rodrigues , Imarilde I. Giusti , Ivo A. Nesralla, Paulo R. L. Prates , Roberto T. Sant’Anna, Nance B. Nardi , Renato A. K. Kalil 6 Rev Bras Cir Cardiovasc 2011;26(4):635-46 REVIEW ARTICLE
Gene Therapy, 2019
Cell therapy has shown impressive effects in experimental cardiomyopathy models. To a lesser extent, gene therapy has also been studied. In both cases, translation to clinical therapy has been disappointing. This paper is intended to describe the experience and achievements of a multicenter working group located in Porto Alegre, southern Brazil, in experimental and translational research projects for cell-based and gene therapy methods in the treatment of dilated and ischemic cardiomyopathies. The results of preclinical and clinical studies showed that bone marrow mononuclear stem cells indeed have an effect in improving myocardial perfusion and contractile function, but the overall results are poorly translated to the clinical level. Gene therapy studies with direct myocardial Conflict of interest The authors declare that they have no conflict of interest.
Gene Therapy for Myocardial Angiogenesis
Circulation, 1998
Background-We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. Methods and Results-VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF 165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTxϭ75Ϯ15/min versus post-GTxϭ80Ϯ16/min, PϭNS), systolic BP (114Ϯ7 versus 118Ϯ7 mm Hg, PϭNS), or diastolic BP (57Ϯ2 versus 59Ϯ2 mm Hg, PϭNS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm 3 , and total chest tube drainage was 110 to 395 cm 3. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthe-siaϭ4.8Ϯ0.4 versus postanesthesiaϭ4.1Ϯ0.3 versus 24 hours postoperativeϭ6.3Ϯ0.8, Pϭ0.02). Time to extubation after closure was 18.4Ϯ1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] useϭ53.9Ϯ10.0/wk pre-GTx versus 9.8Ϯ6.9/wk post-GTx, PϽ0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (nϭ3) or improved (nϭ2, mean increase in LVEFϭ5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients. Conclusions-This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.
Gene Therapy for Cardiovascular Diseases
Annals of Medicine, 1996
Gene therapy is a rapidly evolving field of medicine, which potentially offers new treatments for cardiovascular diseases. With the use of gene transfer methods it is possible to modify somatic cells in blood vessels and myocardium to overexpress or inhibit pathologically important proteins and achieve therapeutic effects. Prevention of restenosis after vascular interventions such as percutanous coronary angioplasty (PTCA), percutanous peripheral angioplasty (PTA) or stent implantation, prevention of venous graft failures and therapeutic angiogenesis are the major aims of experimental studies and clinical gene therapy. The promise of gene therapy in the treatment of cardiovascular diseases remains high. Experimental studies have established the proof of principle that gene transfer to cardiovascular system can achieve therapeutic effects. First human clinical trials provided initial evidence of the feasibility and safety of the novel therapy. There are also first successful reports on the prevention of neointimal hyperplasia and promotion of therapeutic angiogenesis in clinical trials. However, there are still important questions regarding utility, efficiency and safety of gene therapy in the treatment of cardiovascular diseases. In this review we discuss the rapid progress in cardiovascular gene therapy, the development of delivery systems and vectors, most promising therapeutic genes and results of the recent human clinical trials.
Gene Therapy for the Heart Lessons Learned and Future Perspectives
Circulation Research, 2020
While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, ...
Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects
Circulation Research, 2001
Clinical trials of cardiovascular gene therapy, whether using viral (53%) or nonviral (47%) vectors, have thus far disclosed no evidence indicative of inflammatory or other complications, including death, directly attributable to the vector used. Indeed, despite the fact that initial trials of cardiovascular gene therapy targeted patients with end-stage vascular disease, including critical limb ischemia and refractory myocardial ischemia, the mortality for patients enrolled in clinical trials of cardiovascular gene therapy reported to date compares favorably with mortality for similar groups of patients in contemporary controlled studies of medical or interventional therapies. The most common morbidity reported after cardiovascular gene transfer is lower extremity edema; in contrast to data involving genetically engineered mice, however, evidence of life- or limb-threatening edema has not been described in any patients, including patients after gene transfer for myocardial ischemia....