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

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

2 GENE THERAPY 1. CORRECT GENES 2. CURE WITH GENES

3 WHAT IS GENE? DNA ( deoxyribonucleic acid ) - DOUBLE HELICAL STRUCTURE GENE ; PART OF DNA THAT LEADS TO EXPRESSION gene gene gene

4 WHAT IS GENE? DNA ( deoxyribonucleic acid ) -Double helical structure - IN THE NUCLEUS

5 WHAT IS GENE? DNA ( deoxyribonucleic acid ) - present as allele

6 WHAT IS GENE? DNA ( deoxyribonucleic acid ) - each allele is from father and mother + = 2n

7 WRINKLED AND STRAIGHT HAIR

8 CENTRAL DOGMA Gene (DNA) BNORMAL GENE RNA protein CORRECTION NORMAL PROTEIN ABNORMAL PROTEIN GENE DISEASE CURE

9 SICKLE CELL ANEMIA

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12 BLESSED OR BUSTED?

13 NATURAL SELECTION NORMAL RBC TARGET OF MALARIA SSA - TOLERANT AGAINST MALARIA NORMAL ENVIRONMENT NO SSA ENDEMIC FOR MALARIA SSA FAVORED

14 GENE THERAPY 1. CORRECT GENES 2. CURE WITH GENES

15 ABNORMAL Gene (DNA) Gene (DNA) Gene (DNA) 정상 Gene (DNA) RNA ABNORMAL protein Gene (DNA) RNA protein

16 GENE THERAPY GENE IN CARRIER TO NUCLEUS

17 Oh! VIRUS

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19 GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE

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21 Ex) cystic fibrosis, Duchenne s muscular dystrophy

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24 ANGIOGENESIS

25 Pathologic condition (Ischemia) Manageable Operation Intervention Un - Manageable no option patient failed Gene therapy

26 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 ischemic peripheral neuropathy

27 Mode of Delivery

28 Improved in Myocardial Perfusion in Ischemic Heart Disease Isner et al Circulation 1998;98:2800

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30 Isner et al Circulation 1998;97:1114 Limb salvage in patients recommended for lower extremity amputation

31 VEGF (vascular endothelial growth factor) - Discovered by N. Ferrara in 1986, 45 kda - subsets of VEGF in human VEGF 121 VEGF 165 VEGF VEGF receptors Exon 1-5 Exon VEGFR-1 ; Flt-1 VEGFR-2 ; KDR/Flk-1 VEGFR-3 ; Flt-4

32 VEGF is induced by ---- Haemodynamics exercise hyperthyroid state drugs Shear stress and stretch on the myocardium Hypoxia Inflammatory responses

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34 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.

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38 Pitfall of Gene Therapy in Cardiovascular system High Mortality? High Morbidity?

39 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

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41 Morbidity Accelerated Atherosclerosis Vascular Malformations Neoplasms Retinopathy Edema Additional Safety Concerns Hypotension Arrhythmias

42 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!

43 Angiopoietin-2 - loosening smooth muscle cells VEGF - growth of endothelial cells ephrin-b2 - morphological arterialization Angiopoietin-1 - growth of smooth muscle cells

44 MYOPATHY ; MORE DIFFICULT CELL THERAPY IS FAVORED, BUT NOT READY

45 YEAR 2053? TREATMENT OF ISCHEMIC HEART DISEASE = ANGIOGENESIS WITH GENE THERAPY + MYOCARDIAL REGENERATION WITH CELL THERAPY