Alberto Crottogini. TCT 2012 - Transcatheter Cardiovascular Therapeutics-. Find more presentations on our web site.

1. Why We Still Believe Angiogenesis Can
Be an Alternative for No-Option
Patients
Alberto Crottogini, MD, PhD
Favaloro University
Buenos Aires, Argentina

2. Disclosure Statement of Financial
Interest
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.

3. pCMVrhVEGF165
lacZ alpha Plac ori
Tn5 /
kanr CMV
Enhancer-
Promoter
3929 bp
Chimeric
SV40 intron
PolyA
VEGF 165

4. Animal models
Chronic myocardial ischemia Acute myocardial infarction
Treated group: pVEGF 3.8 mg
Placebo group: pNull 3.8 mg

5. Arteriolar neoformation
Densidad numérica Densidad de longitud
Numerical density m
Colaterales de 8 a 50 Length densitya 50 m
Colaterales de 8
1,2 placebo 3,0 placebo
1,0
VEGF 2,5
VEGF
Lc (mm / mm )
3
0,8 2,0
Nc (mm-2)
0,6 1,5
0,4 1,0
Pp<<0.02
0,02 P p < 0,02
< 0.02
0,2 0,5
0,0 0,0
Crottogini et al. Hum Gene Ther 14:1307-18,2003

6. Perfusion (SPECT-sestamibi)
Crottogini et al. Hum Gene Ther 14:1307-18,2003

7. Adult cardiomyocyte mitosis
Laguens R et al. Gene Ther 2002; 9:1676-1681

8. pVEGF after AMI: results at 10 days (myoblasts)
Ki 67 (+), SA (+). Connexin 43 (+), SMA (-), Ulex lectin (-)
Vera Janavel et al. Gene Ther 2006; 13:1133-1142

9. pVEGF in AMI: infarct size limitation
Vera Janavel et al. Gene Ther 2006;13:1133-1142
Vera Janavel et al. J Gene Med 2012;14:279-287

10. 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: León Valdivieso, Gustavo Vera Janavel, Alberto Crottogini
Favaloro Foundation University Hospital
Favaloro University

11. GENESIS - I
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

12. Inclusion 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%
Exclusion criteria
• 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

13. Injection procedure
MyoCath ® (Bioheart)
10 intramyocardial
injections of pVEGF
0.38 mg
(total dosis 3.8 mg)
Sherman W. Basic Appl Myol 13:11 (2003)

14. Patients included (n=10)
Edad 70 añ
Age 60 years (46–71)
Sexo masculino n (%)
Male sex n (%) 9 (90)
Clase funcional angor 2
Angina FC 2.5 (2–3)
Dislipemia n (%)
Dyslipidemia n (%) 9 (90)
Ex TBQ n (%) 1
Ex smoker n (%) 10 (100)
Hipertensión arterial n (%)
Arterial hypertension n (%) 7 (70)
Diabetes tipo II n (%)
Type II diabetes n (%) 5 (50)
Enf. vascular periférica n (%)
Peripheral vasc. disease n (%) 4 (40)
IAM previo n (%)
Prior AMI n (%) 8 (80)
Stroke / AIT n (%)
Stroke / TIA n (%) 0
FE 52,1
EF 44.2 % (39–66)
9 (90) CRM previa n (%)
Prior CABG n (%) Reoper
Reoperation: 2 (20)
PTCA previa n (%)
Prior PTCA n (%) 5 (50)

15. Results
• 10 patients included
• follow up:
6 months (n=10)
24 months (n=10)

16. Results: safety
Related adverse effects
• Serious
None
• Not serious
Plasma hVEGF increase (ELISA)
Ventricular arrhythmias (self-controlled)

17. Results
Unrelated adverse effects
Femoral artery thrombosis: 1 (12th week angiography)
Non-ST AMI: 2 (2nd year follow up)

18. Results: angina pectoris
Functional class (CCS)
6 months 24 months
4 4
P < 0.01
P < 0.01
3 3
2 2.6 2 2.6
±0.2 ±0.2
1 1
1.2 1.2
±0.3 ±0.3
0 0

19. Results: quality of life
Seattle Angina Questionnaire
6 months 24 months
100% 100%
P < 0.01 P < 0.01
80% 80%
82.1 82.6
±2.4 ±2.4
60% 60%
56.9 56.9
40% ±3.2 ±3.2
40%
20% 20%

20. Results: myocardial perfusion
Ischemic burden (SDS)
6 months 24 months
25 P < 0.04 25 P < 0.04
20 20
15 15
10 13.4 10
13.4
±2
±2
9.5
5 5
±2.4 7.7
±1.8
0 0

21. Myocardial perfusion (SPECT scan)

22. Results: left ventricular function
Ejection fraction (stress echo)
6 months 24 months
70% 70%
50% 50%
51.6
±3.6 47.8
44.2 44.2 ±2.7
30% ±3.6 30% ±3.6
P < 0.02 P = NS
10% 10%

23. Plasma VEGF levels
ELISA

24. EUROINJECT One Trial: 0.5 mg pVEGF
NORTHERN Trial: 2 mg pVEGF

25. 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.

26. Gene therapy for IHD
Unresolved issues:
• Single or combined therapy?
• Single or repeated administration?
• Vector?
• Route?
• Dosis?
•Which patients?

27. Favaloro University University Hospital
Rubén Laguens Liliana Favaloro
Gustavo Vera Janavel Mirta Diez
Daniela Olea Oscar Mendiz
Patricia Cabeza Meckert León Valdivieso
Andrea De Lorenzi Roxana Ratto
Luis Cuniberti Gustavo Lev
María Inés Besansón Claudia Cortés
Pedro Iguain Mariana Daicz
Marta Tealdo Fabián Salmo
Fabián Vaisbuj
Biosidus
Andrés Bercovich
Carlos Melo Supported by grants from the
Guillermo Garelli
National Agency for the Promotion
Genaro Montero
Mariana Papouchado of Science and Technology,
Norberto Judewicz Argentina
Marcelo Criscuolo

28. Thank you !

29. Adult cardiomyocyte mitosis
Laguens R et al. Gene Ther 2002; 9:1676-1681
Recruitment and activation of myoblasts
Laguens R et al. Gene Ther 2002; 9:1676-1681

30. Bioethics Committee Approvals
Protocolo y estudios pre-clínicos: 19 Nov 2001
Enmienda #1: 17 Mar 2004
Sub-Estudio en Tecnología Médica: 2 Mar 2005
Enmienda #2 y Consentimiento Informado última versión: 4 Oct 2006 (Acta n° 129)
Enmienda #3: 18 Jul 2007 Ref. DDI (785) 2001 n° 150/05 (Acta n° 161)
ANMAT Approvals
Protocolo y estudios pre-clínicos: Disposición ANMAT n° 4063 (1 Ago 2003). Exp. n° 1-47-12822/01-6
Sub-Estudio: Nota Direcc. Tecnología Médica n° 676 (30 Jun 2005). Exp. n° 1-47-2142/04-0
Enmienda #1: Nota Direcc. Evaluación de Medicamentos (4 Jul 2005). Exp. n° 1-47-2142/04-0
Enmienda #2. Nota Direcc. Evaluación de Medicamentos (23 Nov 2006) Exp. n° 1-47-20820/06-7
Enmienda #3. Nota Direcc. Evaluación de Medicamentos (23 Jul 2007). Exp. n° 1-47-14493/07-3