Università e Azienda Ospedaliera di Perugia

Cardiologia

e

Fisiopatologia Cardiovascolare

Università e Azienda Ospedaliera di Perugia

Cardiologia

e

Fisiopatologia Cardiovascolare

Terapia Cellulare in Cardiologia

Giuseppe Ambrosio

Terapia Cellulare in Cardiologia

Giuseppe Ambrosio

Il trapianto cellulare come alternativa al trapianto d'organo: studio dei processi di crescita e

differenziamento delle cellule staminali orientate verso fenotipi cardiovascolari

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 RICERCADipartimento 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

Circulation, November 2005Circulation, November 2005

Therapeutic AngiogenesisTherapeutic 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?

Angiogenesi Terapeutica:Possibili Approcci

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

Therapeutic AngiogenesisTherapeutic 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?

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

(Safi J et al, Microvascular Research 1999)

Therapeutic AngiogenesisTherapeutic 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?

(Safi J et al, Microvascular Research 1999)

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Capillary DensityCapillary Density Arteriolar DensityArteriolar Density

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

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

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

(Safi J et al, Microvascular Research 1999)

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Therapeutic AngiogenesisTherapeutic 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?

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

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

Therapeutic AngiogenesisTherapeutic 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?

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

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

Therapeutic Angiogenesis:Potential Risks

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

Therapeutic AngiogenesisTherapeutic 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?

The reason is an optical illusion called the Ponzo Illusion, after Italian physicist Mario Ponzo, who first demonstrated it in 1913. In determining the size of an object our mind is influenced by the background

The reason is an optical illusion called the Ponzo Illusion, after Italian physicist Mario Ponzo, who first demonstrated it in 1913. In determining the size of an object our mind is influenced by the background

Actually, they’re the same!

The Ponzo Effect:Endothelial Progenitor Cells Appear on the Horizon

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 PattersonCam Patterson

Cell Therapy for Acute Myocardial Infarction: Curb Your Enthusiasm?

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

Rosenzweig, A. N Engl J Med 2003

Three Stages in the Movement of Endothelial Progenitor Cellsfrom Bone Marrow to Vascular Endothelium

Three Stages in the Movement of Endothelial Progenitor Cellsfrom Bone Marrow to Vascular Endothelium

• 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)

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

(Safi J et al, Microvascular Research 1999)

(Safi J et al, Microvascular Research 1999)

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Adenovirus-Mediated Acidic Fibroblast Growth Factor Gene Transfer Induces Angiogenesis in the

Nonischemic Rabbit Heart

Effect of Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells

in Nude Mice Subjected to Myocardial Ischemia

Effect of Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells

in Nude Mice Subjected to Myocardial Ischemia

(Kawamoto et al, Circulation 2003)(Kawamoto et al, Circulation 2003)

The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis

The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis

(Henry et al, Circulation 2003)

Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris

Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris

(Grines CL, Circulation 2002)(Grines CL, Circulation 2002)

Aicher A, et al Circulation 2003 Aicher A, et al Circulation 2003