why we still believe angiogenesis can be an alternative for no-option patients
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7/29/2019 Why We Still Believe Angiogenesis Can Be an Alternative for No-Option Patients
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Why We Still Believe Angiogenesis Can
Be an Alternative for No-Option
Patients
Alberto Crottogini, MD, PhD
Favaloro UniversityBuenos Aires, Argentina
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I, Alberto Crottogini, DO NOT have a
financial interest/arrangement or affiliation
with one or more organizations that could be
perceived as a real or apparent conflict of
interest in the context of the subject of this
presentation.
Disclosure Statement of Financial
Interest
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3929 bp
CMV
Enhancer-Promoter
VEGF 165
Chimeric
intronSV40
PolyA
Tn5 /
kanr
lacZ alpha Plac ori
pCMVrhVEGF165
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Animal models
Treated group: pVEGF 3.8 mg
Placebo group: pNull 3.8 mg
Acute myocardial infarctionChronic myocardial ischemia
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Arteriolar neoformation
Crottogini et al. Hum Gene Ther14:1307-18,2003
Densidad numricaColaterales de 8 a 50 m
p < 0,02
0,0
0,2
0,4
0,6
0,8
1,0
1,2
Nc(mm-2)
placebo
VEGF
Densidad de longitudColaterales de 8 a 50 m
p < 0,02
0,0
0,5
1,0
1,5
2,0
2,5
3,0
Lc(mm/
mm
3)
placebo
VEGF
Numerical density Length density
P < 0.02P < 0.02
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Perfusion (SPECT-sestamibi)
Crottogini et al. Hum Gene Ther14:1307-18,2003
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Laguens Ret al. Gene Ther 2002; 9:1676-1681
Adult cardiomyocyte mitosis
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pVEGF after AMI: results at 10 days (myoblasts)
Vera Janavelet al. Gene Ther 2006; 13:1133-1142
Ki 67 (+), SA (+). Connexin 43 (+), SMA (-), Ulex lectin (-)
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pVEGF in AMI: infarct size limitation
Vera Janavelet al. Gene Ther 2006;13:1133-1142
Vera Janavelet al. J Gene Med 2012;14:279-287
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Safety of High-Dose Plasmid-Mediated VEGF Gene
Transfer in Patients with Severe Ischemic Heart Disease
(GENESIS-I). A Phase I, Open-Label, Two Years Follow-
up Trial.
Principal Investigators : Liliana Favaloro, Mirta Diez, Oscar Mendiz,
Co-investigators: Len Valdivieso, Gustavo Vera Janavel, Alberto Crottogini
Favaloro Foundation University Hospital
Favaloro University
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Objective
To evaluate the safety (primary obj.) and the efficacy (secondary
obj.) of the transendocardial injection of high dose pVEGF
Design
Prospective, Open-label,
Uncontrolled
GENESIS - I
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Inclusion criteria
Exclusion criteria
Signing the written, witnessed informed consent
Symptomatic stable chronic angina
Optimal medical treatment, no chance for revascularization (CABG, PCTA)
Ischemia and/or myocardial viability (SPECT, echo)
Ejection fraction 30%
Unstable angina pectoris
AMI within last month, stroke within 3 last months
Angiogenesis-related diseases (cancer, retinopathy, etc)
Prosthetic aortic valve, wall thickness < 5 mm
Other standard criteria
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Injection procedure
MyoCath (Bioheart)
Sherman W. Basic Appl Myol 13:11 (2003)
10 intramyocardialinjections of pVEGF
0.38 mg
(total dosis 3.8 mg)
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Patients included (n=10)
Age 60 years (4671)
Male sex n (%) 9 (90)
Angina FC 2.5 (23)
Dyslipidemia n (%) 9 (90)
Ex smoker n (%) 10 (100)
Arterial hypertension n (%) 7 (70)
Type II diabetes n (%) 5 (50)
Peripheral vasc. disease n (%) 4 (40)
Prior AMI n (%) 8 (80)
Stroke / TIA n (%) 0
EF 44.2 % (3966)
9 (90)
Reoperation: 2 (20)
Prior PTCA n (%) 5 (50)
Prior CABG n (%)
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Results
10 patients included
follow up:
6 months (n=10)
24 months (n=10)
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Results: safety
Related adverse effects
Serious
Not serious
None
Plasma hVEGF increase (ELISA)
Ventricular arrhythmias (self-controlled)
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Results
Unrelated adverse effects
Femoral artery thrombosis: 1 (12th week angiography)
Non-ST AMI: 2 (2nd year follow up)
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Functional class (CCS)
Results: angina pectoris
6 months 24 months
0
1
2
3
4
P < 0.01
2.6
0.2
1.2
0.3
0
1
2
3
4
P < 0.01
1.2
0.3
2.6
0.2
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Seattle Angina Questionnaire
20%
40%
60%
80%
100%
56.93.2
82.1
2.4
P < 0.01
Results: quality of life
6 months 24 months
20%
40%
60%
80%
100%
56.93.2
82.6
2.4
P < 0.01
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Results: myocardial perfusion
Ischemic burden (SDS)
6 months 24 months
0
5
10
15
20
25
13.4
2
9.5
2.4
P < 0.04
0
5
10
15
20
25
13.4
2
7.7
1.8
P < 0.04
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Myocardial perfusion (SPECT scan)
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Results: left ventricular function
Ejection fraction (stress echo)
6 months 24 months
10%
30%
50%
70%
44.2
3.6
51.6
3.6
P < 0.02
10%
30%
50%
70%
44.2
3.6
47.82.7
P = NS
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Plasma VEGF levels
ELISA
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EUROINJECT One Trial: 0.5 mg pVEGF
NORTHERN Trial: 2 mg pVEGF
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Conclusions
Intramyocardial administration of pVEGF 3.8 mg with
injection catheter:
Was safe
Improved myocardial perfusion
Improved LV function at 6 but not at 24 months
Reduced angina functional class and improved quality of life
These results must be confirmed on larger populations in
randomized, double-blind, placebo-controlled clinical trials.
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Gene therapy for IHD
Single or combined therapy?
Single or repeated administration?
Vector?
Route?
Dosis?
Which patients?
Unresolved issues:
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Favaloro University
Rubn Laguens
Gustavo Vera Janavel
Daniela OleaPatricia Cabeza Meckert
Andrea De Lorenzi
Luis Cuniberti
Mara Ins Besansn
Pedro Iguain
Marta Tealdo
Andrs Bercovich
Carlos MeloGuillermo Garelli
Genaro Montero
Mariana Papouchado
Norberto Judewicz
Marcelo Criscuolo
Liliana Favaloro
Mirta Diez
Oscar MendizLen Valdivieso
Roxana Ratto
Gustavo Lev
Claudia Corts
Mariana Daicz
Fabin Salmo
Fabin Vaisbuj
Biosidus
Supported by grants from theNational Agency for the Promotion
of Science and Technology,
Argentina
University Hospital
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Thank you !
Adult cardiomyocyte mitosis
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Laguens Ret al. Gene Ther 2002; 9:1676-1681
Adult cardiomyocyte mitosis
Laguens Ret al. Gene Ther 2002; 9:1676-1681
Recruitment and activation of myoblasts
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Bioethics Committee Approvals
Protocolo y estudios pre-clnicos: Disposicin ANMAT n 4063 (1 Ago 2003). Exp. n 1-47-12822/01-6
Sub-Estudio: Nota Direcc. Tecnologa Mdica n 676 (30 Jun 2005). Exp. n 1-47-2142/04-0
Enmienda #1: Nota Direcc. Evaluacin de Medicamentos (4 Jul 2005). Exp. n 1-47-2142/04-0
Enmienda #2. Nota Direcc. Evaluacin de Medicamentos (23 Nov 2006) Exp. n 1-47-20820/06-7
Enmienda #3. Nota Direcc. Evaluacin de Medicamentos (23 Jul 2007). Exp. n 1-47-14493/07-3
ANMAT Approvals
Protocolo y estudios pre-clnicos: 19 Nov 2001Enmienda #1: 17 Mar 2004
Sub-Estudio en Tecnologa Mdica: 2 Mar 2005
Enmienda #2 y Consentimiento Informado ltima versin: 4 Oct 2006 (Acta n 129)
Enmienda #3: 18 Jul 2007 Ref. DDI (785) 2001 n 150/05 (Acta n 161)