why we still believe angiogenesis can be an alternative for no-option patients

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 !



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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)

why we still believe angiogenesis can be an alternative for no-option patients

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