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GENE THERAPY IN CARDIOVASCULAR DISEASES

ASAN MEDICAL CENTERKI HOON HAN MD

GENE THERAPY

1. CORRECT GENES

2. CURE WITH GENES

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )- DOUBLE HELICAL STRUCTURE

GENE ; PART OF DNA THAT LEADS TO EXPRESSION

gene genegene

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )-Double helical structure

- IN THE NUCLEUS

WHAT IS GENE ?

DNA ( deoxyribonucleic acid )- present as allele

WHAT IS GENE ?

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

+ = 2n

WRINKLED AND STRAIGHT HAIR

CENTRAL DOGMA

RNAprotein

GENE DISEASE

ABNORMALPROTEIN

ABNORMAL GENE

NORMALPROTEIN CURE

Gene (DNA)

CORRECTION

SICKLE CELL ANEMIA

BLESSED OR BUSTED ?

NATURAL SELECTION

NORMAL RBC – TARGET OF MALARIASSA - TOLERANT AGAINST MALARIA

NORMAL ENVIRONMENTNO SSA

ENDEMIC FOR MALARIASSA FAVORED

GENE THERAPY

1. CORRECT GENES

2. CURE WITH GENES

RNAprotein

ABNORMALGene (DNA)

RNAABNORMAL

proteinGene (DNA)

Gene (DNA)정상Gene (DNA)

Gene (DNA)

GENE THERAPY

GENE IN CARRIER

TO NUCLEUS

Oh! VIRUS

GENE THERAPY IN CARDIOVASCULAR DISEASES

ANGIOGENESISHEART FAILURE

Ex) cystic fibrosis, Duchenne’s muscular dystrophy

ANGIOGENESIS

Pathologic condition(Ischemia)

failed

OperationManageable

Intervention

Un - Manageable“ no option patient “

Gene therapy

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

Mode of Delivery

Improved in Myocardial Perfusion in Ischemic Heart Disease

Isner et alCirculation 1998;98:2800

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Isner et alCirculation 1998;97:1114

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

VEGF is induced by ----

Haemodynamicsexercisehyperthyroid statedrugs

Shear stress and stretch on the myocardiumHypoxiaInflammatory responses

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.

Pitfall of Gene Therapy in Cardiovascular system

High Mortality ?

High Morbidity ?

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

Morbidity

Accelerated AtherosclerosisVascular MalformationsNeoplasmsRetinopathyEdemaAdditional Safety Concerns

HypotensionArrhythmias

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 !

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

MYOPATHY ;MORE DIFFICULTCELL THERAPY IS FAVORED, BUT NOT READY

YEAR 2053 ?

TREATMENT OF ISCHEMIC HEART DISEASE

= ANGIOGENESIS WITH GENE THERAPY+

MYOCARDIAL REGENERATION WITH CELL THERAPY