Why We Still Believe Angiogenesis Can Be an Alternative for No-Option Patients

Alberto Crottogini, MD, PhD Favaloro University Buenos Aires, Argentina

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.

pCMVrhVEGF165
lacZ alpha Plac

ori

Tn5 / kanr

CMV EnhancerPromoter
3929 bp

SV40 PolyA

Chimeric intron

VEGF 165

Animal models
Chronic myocardial ischemia Acute myocardial infarction

Treated group: pVEGF 3.8 mg Placebo group: pNull 3.8 mg

Arteriolar neoformation

Numerical density m Colaterales de 8 a 50

1,2 1,0

Densidad numrica

Length densitya 50 m Colaterales de 8

placebo VEGF
3 Lc (mm / mm )

Densidad de longitud
placebo VEGF

3,0 2,5 2,0 1,5 1,0 0,5 0,0

Nc (mm-2)

0,8 0,6 0,4

Pp<<0.02 0,02
0,2 0,0

P p < 0,02 < 0.02

Crottogini et al. Hum Gene Ther 14:1307-18,2003

Perfusion (SPECT-sestamibi)

Crottogini et al. Hum Gene Ther 14:1307-18,2003

Adult cardiomyocyte mitosis

Laguens R et al. Gene Ther 2002; 9:1676-1681

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

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

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 Followup Trial.
Principal Investigators : Liliana Favaloro, Mirta Diez, Oscar Mendiz, Co-investigators: Len Valdivieso, Gustavo Vera Janavel, Alberto Crottogini
Favaloro Foundation University Hospital
Favaloro University

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

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

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)

Patients included (n=10)

Edad
Age Male sex n (%) Angina FC Dyslipidemia n (%) Ex smoker n (%) Arterial hypertension n (%) Type II diabetes n (%) Peripheral vasc. disease n (%) Prior AMI n (%) Stroke / TIA n (%) EF 60 years (4671)

70 a

Sexo masculino n (%)

9 (90)

Clase funcional angor

2.5 (23)

Dislipemia n (%)
9 (90)

Ex TBQ n (%)
10 (100)

Hipertensin arterial n (%)

7 (70)

Diabetes tipo II n (%)

5 (50)

Enf. vascular perifrica n (%)

4 (40)

IAM previo n (%)

8 (80)

Stroke / AIT n (%)

0

FE
44.2 % (3966) 9 (90) Prior CABG n (%) Reoperation: 2 (20)

52,1

CRM previa n (%)

Reoper PTCA previa n (%)

Prior PTCA n (%)

5 (50)

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

Results: safety
Related adverse effects
Serious None Not serious Plasma hVEGF increase (ELISA)

Ventricular arrhythmias (self-controlled)

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

Results: angina pectoris

Functional class (CCS) 24 months
4
P < 0.01 P < 0.01

6 months
4

2.6 0.2

2.6 0.2

1
1.2 0.3

1
1.2 0.3

Results: quality of life

Seattle Angina Questionnaire 6 months
100%
P < 0.01

24 months
100%
P < 0.01

80%
82.1 2.4

80%
82.6 2.4

60%
56.9 3.2

60%
56.9 3.2

40%

40%

20%

20%

Results: myocardial perfusion

Ischemic burden (SDS)
6 months
25

24 months
25

P < 0.04

P < 0.04

20

20

15

15

10

13.4 2 9.5 2.4

10

13.4 2 7.7 1.8

Myocardial perfusion (SPECT scan)

Results: left ventricular function

Ejection fraction (stress echo)
6 months
70% 70%

24 months

50%
51.6 3.6

50%
47.8 2.7 P = NS

30%

44.2 3.6 P < 0.02

30%

44.2 3.6

10%

10%

Plasma VEGF levels

ELISA

EUROINJECT One Trial: 0.5 mg pVEGF

NORTHERN Trial: 2 mg pVEGF

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.

Gene therapy for IHD

Unresolved issues:
Single or combined therapy?

Single or repeated administration?

Vector? Route? Dosis? Which patients?

Favaloro University
Rubn Laguens Gustavo Vera Janavel Daniela Olea Patricia Cabeza Meckert Andrea De Lorenzi Luis Cuniberti Mara Ins Besansn Pedro Iguain Marta Tealdo

University Hospital
Liliana Favaloro Mirta Diez Oscar Mendiz Len Valdivieso Roxana Ratto Gustavo Lev Claudia Corts Mariana Daicz Fabin Salmo Fabin Vaisbuj

Biosidus
Andrs Bercovich Carlos Melo Guillermo Garelli Genaro Montero Mariana Papouchado Norberto Judewicz Marcelo Criscuolo

Supported by grants from the National Agency for the Promotion of Science and Technology, Argentina

Thank you !

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

Bioethics Committee Approvals

Protocolo y estudios pre-clnicos: 19 Nov 2001 Enmienda #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)

ANMAT 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