Angiogenesis Ppt Powerpoint Presentation slides-Medical Slideshow Therapeutic Angiogenesis

Angiogenesis

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Slide 1 :

Angiogenesis Dr Julian Gunn MA, MD, MRCP Senior Lecturer/Hon. Consultant Cardiologist, Sheffield Teaching Hospitals NHS Trust

Slide 2 :

Angiogenesis Why does it matter to me?-1a

Slide 3 :

Angiogenesis Why does it matter to me?-1b

Slide 4 :

Angiogenesis Why does it matter to me?-2

Slide 5 :

Angiogenesis Why does it matter to me?-3 Before gene therapy After gene therapy

Slide 6 :

Angiogenesis Why does it matter to me?-4

Slide 7 :

Angiogenesis Why does it matter to me?-5

Slide 8 :

Definitions Vasculogenesis Formation of new vessels from EC precursors (angioblasts) Angiogenesis Formation of new vessels from pre- existing BV by sprouting Arteriogenesis Subsequent stabilisation and maturation Collateralisation Enlarging existing vessels as bridges between networks (Myogenesis)

Slide 9 :

Angiogenesis Physiological roles

Slide 10 :

Angiogenesis Dysregulation in disease states

Slide 11 :

Angiogenesis Dysregulation in disease states

Slide 12 :

Angiogenesis History-1 1787 John Hunter: ‘angiogenesis’ (antler) 1935 Arthur Tremain: angiogenesis in placenta 1971 Judah Folkman: tumour depends on angiogenesis 1984 Yuen Shing: bFGF purified 1989 Napoleone Ferrara: VEGF discovered 1989 Carl White: treated pulmonary haemangioma with Ifn-a2a 1992 Cancer trial with TNP-470 1997 Michael O’Reilly: cancer regression with angiostatin and endostatin

Slide 13 :

Angiogenesis History-2 1998 TMR FDA-approved for CHD 1999 Anti-angiogenic trials: 46 (cancer); 5 (macular degeneration); 1 (diabetic retinopathy); 4 (psoriasis) 1999 Pro-angiogenesis trials: 5 (CHD); 5 (PVD); 1 (stroke); 10 (wound healing)

Slide 14 :

BV development Carmeliet P. Nature Med 2003;9:653-60

Slide 15 :

BV development Carmeliet P. Nature Med 2003;9:653-60

Slide 16 :

Angiogenesis Lessons from tumour biology

Slide 17 :

Angiogenesis Command and control Fam NP et al. Circulation 2003;108:2613-8

Slide 18 :

Angiogenesis Balance of activators and inhibitors + Proteins - Proteins aFGF, bFGF, EGF, HGF, TSP-1 PD-EGF, VEGF(A-E), PlGF Angiostatin Angiopoietins 1 and 2 Endostatin G-CSF PL 16kd IL8 MMPI Scatter F Platelet F-4 TGF-a Genistein TNF- a PlPRP TGFß + Small molecules Ifn-a Adenosine 1-butyryl glycerol Nicotinamide PGE1 and E2 NO

Slide 19 :

Angiogenesis Role in cardiac disease Ischaemia Chronic arterial occlusions antegrade collaterals retrograde collaterals Heart failure Atherosclerosis Restenosis AVMs

Slide 20 :

Angiogenesis Potential stimuli in CHD Embryology Hypoxia Tissue injury Pressure/shear? Inflammation Coagulation Simons M et al. Nature Reviews 2003;2:1-9

Slide 21 :

Angiogenic strategies {Physical: Needle, RF, laser (PMR/TMR)} Protein: VEGF, bFGF etc Gene: naked DNA/plasmid/virus Cell: endothelial cell/ BM stem cell Routes -Intra-arterial -Intra-mural -Peri-vascular -Intra-muscular -pericardial

Slide 22 :

Angiogenesis Animal studies-PVD VEGF/aFGF/bFGF/ (protein mostly) IA/IM Rabbit/mouse + EC proliferation + collateral visualisation + capillary density + calf BP + Doppler arterial flow + thigh oximetry

Slide 23 :

Angiogenesis Animal studies-IHD VEGF/aFGF/bFGF/ (protein mostly;occ gene+adeno vector) IA/perivascular/pericardium Dog/pig – gradual ameroid constrictor + regional blood flow + collateral vessels (placebo catch-up) - infarct size + systolic function

Slide 24 :

Angiogenesis Clinical PVD:a gene approach (phVEGF165) Pre 4 wks Isner JM et al. Lancet 1996;348:370-4 N=1 Severe PVD Limb threatened Not for PTA/Sx No cancer or DM retinopathy Naked cDNA Hydrogel balloon 1% transfection Nb. Spider naevi

Slide 25 :

Angiogenesis Clinical trial in PVD N=9 pts, 10 limbs Plasmid phVEGF165 gene transfer 2 x 2µg boluses i.m. 4 wks apart 6/12: clinically improved in 8/10 Improved ulceration in 4/7 45% + ABPI MRI flow + in 8/10 New collaterals in 6/10 Walking time + from 4.2 to 6.7 min No unwanted BV development elsewhere Baumgartner I et al. Circulation 1998;97:1114-23

Slide 26 :

Angiogenesis Clinical effect in PVD Pre Post

Slide 27 :

TRAFFIC TheRapeutic Angiogenesis with rFGF2 for Intermittent Claudication Lederman RJ N=150 (ongoing) Efficacy of rFGF-2 at improving claudication Moderate/severe claudication + infra-inguinal obstruction ABI<0.80 Intra-arterial injection Randomised: Placebo/single dose/double dose Endpoints: exercise capacity

Slide 28 :

Angiogenesis a GF approach in CAD Intra-operative injection of FGF-1 to the human ischaemic myocardium Schumacher et al. Circulation 1998;97:645-50

Slide 29 :

Angiogenesis Early experience in IHD N=40 pts Multivessel CAD (incl distal LAD/ D1) LIMA + randomised to i.m. bFGF/ placebo 12 wk angio: capillary network in bFGF not control 2-3 fold + vascular density by grey scale No clinical follow-up Schumacher et al. Circulation 1998;97:645-50

Slide 30 :

Angiogenesis for IHD Grey scale

Slide 31 :

Angiogenesis Clinical trials in IHD (DMR/TMR) FIRST FGF-2 Initiating Revascularization Support Trial VIVA VEGF In Vascular Angiogenesis AGENT Angiogenic GENe Therapy REVASC Randomised Evaluation of VEGF for Angiogenesis in Severe Coronary disease

Slide 32 :

Angiogenesis mechanical approaches: the reality

Slide 33 :

FIRST FGF-2 Initiating Revascularization Support Trial Simons M. N=337; complete Efficacy of rFGF-2 in patients with severe CAD No revascularization option Reversible ischaemia on scintigraphy Randomised: Placebo/low/medium/high dose IC 2x 10min infusions 10mL Endpoints: exercise time; angiographic assessment; angina 180d: no differences in these parameters (?elderly) Circulation 2002;105:788-93

Slide 34 :

VIVA VEGF In Vascular Angiogenesis Henry TD et al N=178; complete Efficacy of rhVEGF-1 Stable angina with reversibility (SPECT) Poor candidate for PCI/CABG Method: I.c. infusion x1 + 3 iv doses Double-blind, placebo vs low vs high dose Endpoints: treadmill time; angina class; angiographic collaterals; perfusion; QOL No difference in any of the 3 parameters (!high dose, day 120) Prominent placebo effect Circulation 2003;107:1359-65

Slide 35 :

AGENT Angiogenic GENe Therapy Grines CL et al. N=79 (complete) 1, 2 or 3 VD Efficacy of ad5-FGF4 gene Randomised to i.c. x1 ad5-FGF4 gene/ placebo Transient +liver enz (2); fever (3) Endpoints: ETT parameters 4 and 12/52: no difference except high dose Circulation 2002;105:1291-7

Slide 36 :

REVASC Randomised Evaluation of VEGF for Angiogenesis in Severe Coronary disease Stewart DJ. N=71 Advanced angina No options for conventional revascularisation Efficacy of Ad-VEGF121 Randomised: mini-thoracotomy + Ad-VEGF121 /best medical ETT parameters improved Angina improved (but unblinded) No difference in adverse events Circulation 2002;106:2986a

Slide 37 :

Phase 1-2 placebo-controlled, double-blind, dose-escalating trial of myocardial VEGF-2 gene transfer by catheter delivery in patients with chronic myocardial ischaemia Losordo DW et al N=19 pts CCS III-IV Not candidates for conventional revascularisation Plasmid VEGF-2 or placebo i.m. Percutaneous approach: NOGA mapping 6 injections Endpoints: angina, exercise time, QOL, scintigraphy, mapping No complications Significant improvement in angina; +ve trend to ETT and QOL Significant improvement in scintigraphy and electro-mech mapping Circulation 2002;105:2012-8

Slide 38 :

KAT Kuopio Angiogenesis Trial Hedman M et al N=103 pts CCS II-III Aim to prevent restenosis Efficacy of ad-VEGF (37),VEGF-plasmid-liposome (28) and Ringers (38) Dispatch catheter after POBA and before stenting 6 month QCA: no difference between groups Circulation 2003;107:2677-83

Slide 39 :

Angiogenesis a stem cell approach

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BONE MARROW A stem cell approach to IHD Leon MB et al N=17 (active) Angina III/IV +ve ETT Maximum medical therapy Poor candidate for conventional revascularisation Severe lesion in conduit Biosense™ percutaneous injection system Harvest autologous mononuclear BM precursors Results pending

Slide 41 :

Stem cells for AMI Strauer BE et al (1) and Assmus B et al (2) Autologous BM cells (1) or circulating EPC (2) PCI infarct artery 12-24h: std Rx vs cells 4-9d: cells isolated, cultured, infused i.c. via balloon 3-4/12 f/u: - infarct size + wall motion + perfusion No adverse events 1) Circulation 2002;106:1913-18. 2) Circulation 2002;106:3009-17

Slide 42 :

Angiogenesis Glimpses of the future? Case study-1 Repair of infarcted myocardium by autologous intra-coronary BM cell transfusion Vina R et al, Argentina. 37F, anterior MI, Q waves V1-6, extensive scar on SPECT, EF 30%, LAD stenosis Recanalised LAD, balloon LAD, balloon cardiac vein (‘stagnation’) Harvest BM, infuse 10mLx3 CD34 cells

Slide 43 :

EF increased from 30 to 52%; and exercise capacity to 40 blocks/day. But was this due to therapy or the spontaneously reopened LAD?

Slide 44 :

Angiogenesis Glimpses of the future? Case study-2 Transcoronary venous stem cell implantation in chronic CAD Vina R et al, Argentina. 73M, diabetic, CABG 11 y ago, blocked grafts, severe ischaemia on SPECT 4.5mm OTW balloon great cardiac vein BM harvest mononuclear cells incl. 22x106 CD34 Infuse over 15min

Slide 45 :

Results: Safe, feasible. Some improvement in lateral wall perfusion on SPECT

Slide 46 :

Angiogenesis Conclusions Future potential in ‘unrevascularisable’ patients Over-simplistic approaches for complex process Protein disappointing; gene therapy promising; cells hopeful Safety: local effect without spillover Side-effects: oedema, hypotension (VEGF) Ischaemia-directed angiogenesis: exacerbate atherosclerosis? Durability: regression of new vessels? Control: right mix of medium and SV? Anti-angiogenesis: novel anti-plaque strategy?

Slide 47 :

Angiogenesis for IHD bottom line? Incredible initial results Disappointments Cautious Optimism!

Slide 48 :

Angiogenesis for IHD?

Slide 49 :

Angiogenesis for IHD? Not necessarily! Pre Post PCI!

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