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GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN MEDICAL CENTER KI HOON HAN MD

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Page 1: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

GENE THERAPY IN CARDIOVASCULAR DISEASES

ASAN MEDICAL CENTERKI HOON HAN MD

Page 2: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

GENE THERAPY

1. CORRECT GENES

2. CURE WITH GENES

Page 3: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )- DOUBLE HELICAL STRUCTURE

GENE ; PART OF DNA THAT LEADS TO EXPRESSION

gene genegene

Page 4: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )-Double helical structure

- IN THE NUCLEUS

Page 5: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )- present as allele

Page 6: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )- each allele is from father and mother

+ = 2n

Page 7: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

WRINKLED AND STRAIGHT HAIR

Page 8: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

CENTRAL DOGMA

RNAprotein

GENE DISEASE

ABNORMALPROTEIN

ABNORMAL GENE

NORMALPROTEIN CURE

Gene (DNA)

CORRECTION

Page 9: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

SICKLE CELL ANEMIA

Page 10: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
Page 11: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
Page 12: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

BLESSED OR BUSTED ?

Page 13: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

NATURAL SELECTION

NORMAL RBC – TARGET OF MALARIASSA - TOLERANT AGAINST MALARIA

NORMAL ENVIRONMENTNO SSA

ENDEMIC FOR MALARIASSA FAVORED

Page 14: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

GENE THERAPY

1. CORRECT GENES

2. CURE WITH GENES

Page 15: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

RNAprotein

ABNORMALGene (DNA)

RNAABNORMAL

proteinGene (DNA)

Gene (DNA)정상Gene (DNA)

Gene (DNA)

Page 16: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

GENE THERAPY

GENE IN CARRIER

TO NUCLEUS

Page 17: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

Oh! VIRUS

Page 18: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
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GENE THERAPY IN CARDIOVASCULAR DISEASES

ANGIOGENESISHEART FAILURE

Page 20: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
Page 21: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

Ex) cystic fibrosis, Duchenne’s muscular dystrophy

Page 22: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
Page 23: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
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ANGIOGENESIS

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Pathologic condition(Ischemia)

failed

OperationManageable

Intervention

Un - Manageable“ no option patient “

Gene therapy

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Gene Therapy in Cardiovascular System

Improved in myocardial perfusion in ischemic heart disease

Reduced failure of lower extremity bypass grafts

Limb salvage in patients recommended for lower extremity amputation

Resolution of sensory deficits in patients with ischemicperipheral neuropathy

Page 27: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

Mode of Delivery

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Improved in Myocardial Perfusion in Ischemic Heart Disease

Isner et alCirculation 1998;98:2800

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Lim

b sa

lvag

e in

pat

ient

s rec

omm

ende

d fo

r lo

wer

ext

rem

ity a

mpu

tatio

n

Isner et alCirculation 1998;97:1114

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VEGF (vascular endothelial growth factor)

- Discovered by N. Ferrara in 1986, 45 kDa- subsets of VEGF in human

VEGF 121VEGF 165VEGF 189

- VEGF receptors

VEGFR-1 ; Flt-1VEGFR-2 ; KDR/Flk-1VEGFR-3 ; Flt-4

Exon 1-5

Exon 6 7 8

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VEGF is induced by ----

Haemodynamicsexercisehyperthyroid statedrugs

Shear stress and stretch on the myocardiumHypoxiaInflammatory responses

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Fibroblast growth factor-2 (Basic fibroblast growth factor); 18 kDa

Fibroblast growth factor-1 (Acidic fibroblast growth factor); 16 kDa

- induces proliferation in wide range of cells upon various stimuli such as hypoxia

- control of capillary proliferation during embryogenesis, tumour progression, and wound healing.

Page 35: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
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Pitfall of Gene Therapy in Cardiovascular system

High Mortality ?

High Morbidity ?

Page 39: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

Mortality

- procedural deaths or any deaths attributable to the transgene used.?

; negligible

- d/t the grim prognosis of the patients included in the study ?; yes

Page 40: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy
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Morbidity

Accelerated AtherosclerosisVascular MalformationsNeoplasmsRetinopathyEdemaAdditional Safety Concerns

HypotensionArrhythmias

Page 42: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

FUTURE

- More study to elucidate the detailed mechanisms of angiogenesis- Clarify the safety and accuracy of the current methods of gene delivery- Confirm the long term effect of gene therapy in angiogenesis- Consider the transport of more than one gene to expect the synergistic effect - Be aggressive to fulfill the phase 3 trials !

Page 43: GENE THERAPY IN CARDIOVASCULAR DISEASES ASAN … therapy.pdf · GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE. Ex) cystic fibrosis, Duchenne’s muscular dystrophy

Angiopoietin-2 - loosening smooth muscle cellsVEGF - growth of endothelial cellsephrin-B2 - morphological arterializationAngiopoietin-1 - growth of smooth muscle cells

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MYOPATHY ;MORE DIFFICULTCELL THERAPY IS FAVORED, BUT NOT READY

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YEAR 2053 ?

TREATMENT OF ISCHEMIC HEART DISEASE

= ANGIOGENESIS WITH GENE THERAPY+

MYOCARDIAL REGENERATION WITH CELL THERAPY