Universit

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Università e Azienda Ospedaliera di
PerugiaCardiologiaeFisiopatologia
Cardiovascolare
Terapia Cellulare in Cardiologia Giuseppe
Ambrosio
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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
Il trapianto cellulare come alternativa al
trapianto d'organo studio dei processi di
crescita e differenziamento delle cellule
staminali orientate verso fenotipi cardiovascolari
Responsabile Scientifico dell'Unità operativa
AMBROSIO Giuseppe Perugia
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Circulation, November 2005
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Therapeutic Angiogenesis

• Is it feasible?
• Does it work?
• Is it safe?
• Will it have an impact on clinical practice?

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Angiogenesi TerapeuticaPossibili 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

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Therapeutic Angiogenesis

• Is it feasible?
• Does it work?
• Is it safe?
• Will it have an impact on clinical practice?

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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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Therapeutic Angiogenesis

• Is it feasible?
• Does it work?
• Is it safe?
• Will it have an impact on clinical practice?

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

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

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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
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Therapeutic Angiogenesis

• Is it feasible?
• Does it work?
• Is it safe?
• Will it have an impact on clinical practice?

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Jun 18, 2002 Wrongful death lawsuit filed
against gene therapy group led by 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
Jul 15, 2003 Medical tribunal rejects
wrongful-death suit against late Jeffrey Isner
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Therapeutic AngiogenesisPotential Risks

• Genomic incorporation
• Inflammatory reaction
• Unwanted vascular proliferation
• Growth/spread of tumors
• Paradoxical worsening of Ischemic Heart Disease

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Therapeutic Angiogenesis

• Is it feasible?
• Does it work?
• Is it safe?
• Will it have an impact on clinical practice?

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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
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The Ponzo EffectEndothelial 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
Cam Patterson
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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
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Three Stages in the Movement of Endothelial
Progenitor Cells from Bone Marrow to Vascular
Endothelium
Rosenzweig, A. N Engl J Med 2003
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• 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)
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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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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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Effect of Intramyocardial Transplantation of
Autologous Endothelial Progenitor Cellsin Nude
Mice Subjected to Myocardial Ischemia
(Kawamoto et al, Circulation 2003)
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The VIVA Trial Vascular Endothelial Growth
Factor in Ischemia for Vascular Angiogenesis
(Henry et al, Circulation 2003)
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Angiogenic Gene Therapy (AGENT) Trial in Patients
With Stable Angina Pectoris
(Grines CL, Circulation 2002)
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Aicher A, et al Circulation 2003