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Università e Azienda Ospedaliera di Perugia Cardiologia e Fisiopatologia Cardiovascolare Terapia Cellulare in Cardiologia Giuseppe Ambrosio Terapia Cellulare.

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Presentation on theme: "Università e Azienda Ospedaliera di Perugia Cardiologia e Fisiopatologia Cardiovascolare Terapia Cellulare in Cardiologia Giuseppe Ambrosio Terapia Cellulare."— Presentation transcript:

1 Università e Azienda Ospedaliera di Perugia Cardiologia e Fisiopatologia Cardiovascolare Terapia Cellulare in Cardiologia Giuseppe Ambrosio Terapia Cellulare in Cardiologia Giuseppe Ambrosio

2 Il trapianto cellulare come alternativa al trapianto d'organo: studio dei processi di crescita e differenziamento delle cellule staminali orientate verso fenotipi cardiovascolari MINISTERO DELL'ISTRUZIONE, DELL'UNIVERSITÀ E DELLA RICERCA Dipartimento per la Programmazione il Coordinamento e gli Affari Economici Servizio per lo sviluppo e il Potenziamento delle Attività di ricerca (SSPAR) PNR 2001 (FIRB art.8) D.M. 199 Ric. del 8 marzo 2001 Protocollo: RBNE01HLAK_005 Responsabile Scientifico dell'Unità operativa AMBROSIO Giuseppe Perugia

3 Circulation, November 2005

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5 Therapeutic Angiogenesis Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice? Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice?

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8 Angiogenesi Terapeutica: Possibili Approcci a)Aumento delle concentrazioni locali di fattori angiogenetici Proteina Naked DNA Trasfezione chimica o fisica Trasfezione virale b)Incremento delle Cellule Progenitrici Iniezione diretta Mobilizzazione a)Aumento delle concentrazioni locali di fattori angiogenetici Proteina Naked DNA Trasfezione chimica o fisica Trasfezione virale b)Incremento delle Cellule Progenitrici Iniezione diretta Mobilizzazione

9 Therapeutic Angiogenesis Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice? Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice?

10 Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the Nonischemic Rabbit Heart (Safi J et al, Microvascular Research 1999)

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13 Therapeutic Angiogenesis Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice? Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice?

14 (Safi J et al, Microvascular Research 1999) Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the Nonischemic Rabbit Heart Capillary Density Arteriolar Density

15 Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the Nonischemic Rabbit Heart (Safi J et al, Microvascular Research 1999) Confocal microscopic localization of endothelial constitutive nitric oxide synthase (ecNOS; red fluorescence), and - smooth muscle actin (green fluorescence) in the vascular wall of coronary arterioles from a rabbit injected with aFGF1-154

16 (Safi J et al, Microvascular Research 1999) Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the Nonischemic Rabbit Heart

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18 Therapeutic Angiogenesis Is it feasible? Does it work in patients? Is it safe? Will it have an impact on clinical practice? Is it feasible? Does it work in patients? Is it safe? Will it have an impact on clinical practice?

19 Safety and Feasibility of Catheter-Based Local Intracoronary Vascular Endothelial Growth Factor Gene Transfer in the Prevention of Postangioplasty and In- Stent Restenosis and in the Treatment of Chronic Myocardial Ischemia Hedman et al, Circulation 2003

20 Therapeutic Angiogenesis Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice? Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice?

21 Jun 18, 2002 Wrongful death lawsuit filed against gene therapy group led by Jeffrey Isner Jun 18, 2002 Wrongful death lawsuit filed against gene therapy group led by Jeffrey Isner Jul 15, 2003 Medical tribunal rejects wrongful-death suit against late Jeffrey Isner Jul 15, 2003 Medical tribunal rejects wrongful-death suit against late Jeffrey Isner The suit alleges that Isner and his colleagues took advantage of patients desperation and "all too human desire for a miracle cure" to get them to agree to the procedure

22 Therapeutic Angiogenesis: Potential Risks Genomic incorporation Inflammatory reaction Unwanted vascular proliferation Growth/spread of tumors Paradoxical worsening of Ischemic Heart Disease Genomic incorporation Inflammatory reaction Unwanted vascular proliferation Growth/spread of tumors Paradoxical worsening of Ischemic Heart Disease

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24 Therapeutic Angiogenesis Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice? Is it feasible? Does it work? Is it safe? Will it have an impact on clinical practice?

25 The reason is an optical illusion called the Ponzo Illusion, after Italian physicist Mario Ponzo, who first demonstrated it in In determining the size of an object our mind is influenced by the background Actually, theyre the same!

26 The Ponzo Effect: Endothelial Progenitor Cells Appear on the Horizon The Ponzo effect (i.e., difficulty of assessing the size of an object as it appears over the horizon) is an apt metaphor for new therapeutic ideas, such as the clinical application of EPCs It is too soon to know whether EPCs will rise up to assume their place in the therapeutic armamentarium of cardiologists and other physicians who treat patients with vascular disease The Ponzo effect (i.e., difficulty of assessing the size of an object as it appears over the horizon) is an apt metaphor for new therapeutic ideas, such as the clinical application of EPCs It is too soon to know whether EPCs will rise up to assume their place in the therapeutic armamentarium of cardiologists and other physicians who treat patients with vascular disease Cam Patterson

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29 Cell Therapy for Acute Myocardial Infarction: Curb Your Enthusiasm? Welt and Losordo, Circulation 2006 (Editoriale di commento a BOOST) We remain optimistic regarding the future of cell therapy for cardiac disease. However, the field requires a recommitment to preclinical investigation as a means of better understanding basic mechanisms, and to clinical trial design based on such preclinical data Welt and Losordo, Circulation 2006 (Editoriale di commento a BOOST) We remain optimistic regarding the future of cell therapy for cardiac disease. However, the field requires a recommitment to preclinical investigation as a means of better understanding basic mechanisms, and to clinical trial design based on such preclinical data

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31 Rosenzweig, A. N Engl J Med 2003 Three Stages in the Movement of Endothelial Progenitor Cells from Bone Marrow to Vascular Endothelium Three Stages in the Movement of Endothelial Progenitor Cells from Bone Marrow to Vascular Endothelium

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35 So far, a flurry of small, mostly uncontrolled clinical studies exploring the safety and feasibility of stem cell therapy have been conducted. These studies have used a myriad of different cell types and preparations, each in a small number of patients, with different disease states This preliminary clinical evidence suggests that stem cell therapy might work. However, we should take into account the lessons learned from therapeutic angiogenesis studies, where great expectations raised by open studies have not been confirmed by subsequent randomized trials We advocate to no longer perform small open studies, but to conduct intermediate-size, double-blind, randomized-controlled clinical trials to establish the effects of stem cell therapy on surrogate markers, like LVEF, myocardial perfusion, or exercise capacity So far, a flurry of small, mostly uncontrolled clinical studies exploring the safety and feasibility of stem cell therapy have been conducted. These studies have used a myriad of different cell types and preparations, each in a small number of patients, with different disease states This preliminary clinical evidence suggests that stem cell therapy might work. However, we should take into account the lessons learned from therapeutic angiogenesis studies, where great expectations raised by open studies have not been confirmed by subsequent randomized trials We advocate to no longer perform small open studies, but to conduct intermediate-size, double-blind, randomized-controlled clinical trials to establish the effects of stem cell therapy on surrogate markers, like LVEF, myocardial perfusion, or exercise capacity (Wollert et al, Circulation 2005)

36 Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the Nonischemic Rabbit Heart (Safi J et al, Microvascular Research 1999)

37 Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the Nonischemic Rabbit Heart

38 Effect of Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells in Nude Mice Subjected to Myocardial Ischemia (Kawamoto et al, Circulation 2003)

39 The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis (Henry et al, Circulation 2003)

40 Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris (Grines CL, Circulation 2002)

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42 Aicher A, et al Circulation 2003


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