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
10
11
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
18
19 GENE THERAPY IN CARDIOVASCULAR DISEASES ANGIOGENESIS HEART FAILURE
20
21 Ex) cystic fibrosis, Duchenne s muscular dystrophy
22
23
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
29
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
33
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.
35
36
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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
40
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
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