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Prof. dr. M.C. Verhaar, MD PhD 2

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1 Prof. dr. M.C. Verhaar, MD PhD 2
Stem and Progenitor Cell Therapy in Peripheral Arterial Disease Current knowledge and controversies Drs. M. Teraa, MD 1,2 Prof. dr. M.C. Verhaar, MD PhD 2 Prof. dr. F.L. Moll, MD PhD 1 1 Department of Vascular Surgery, University Medical Center Utrecht, The Netherlands 2 Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands

2 Backgrounds Critical Limb Ischemia (CLI)
Rest pain or tissue necrosis individuals per million persons per year Important functional implications Major impact on quality of life: Worse than in patients with terminal cancer, chronic kidney or heart disease CLI is associated with significant morbidity and mortality: 50% one year amputation free survival

3 Backgrounds CLI New revascularization strategies needed
~40% of the patients not eligible for surgical or endovascular revascularization: Anatomic location of the lesion Extent of disease Extensive co-morbidity No effective pharmacological therapy Amputation often remaining option New revascularization strategies needed Cell therapy is a promising option

4 Origin of the endothelium

5 Backgrounds cell therapy

6 EPCs and therapeutic implications
Endothelial Progenitor Cells (EPC) Neovascularisation after ischemia Glomerular Capillary Repair Rookmaaker, 2002 Pancreas Regeneration Asahara, 1997 Gloerich, 2004

7 Limb salvage after injection of human EPC

8 Gene and growth factor therapy
Pilot studies have shown promising results for: Vascular Endothelial Growth Factor (VEGF) Hepatocyte Growth Factor (HGF) Fibroblast Growth Factor (FGF) Hypoxia Inducible Factor-1α (HIF-1α) Larger trials have shown rather disappointing results What about cell therapy?

9 Cell therapy – TACT Study (2002)
First Clinical trial Pilot study (25 patients) BM-MNC vs saline Significantly improved ABI, TcPO2, rest pain, pain-free walking time at 4 and 24 weeks Randomized trial (22 patients) BM-MNC vs PB-MNC Significant improvement for BM-MNC Adapted from Tateishi-Yuyama et al. Lancet. 2002;360(9331):427-35

10 Current results on cell therapy in CLI
Mainly small non-controlled studies Adapted from Fadini et al. Atherosclerosis. 2010;209(1):10-17

11 Need for confirmation!!! Large randomized controlled trials
More clinical relevant end points: Amputation Mortality Quality of Life Elucidate the black box of cell therapy

12 Black Box Patient characteristics? Administration route? Cell type?
Cell source? Mechanism?

13 Which patient will benefit?
Young vs. Old Diabetics vs. Non-diabetics Male vs. Female Chronic kidney disease BMI Smokers vs. Non-smokers Fontaine III vs. Fontaine IV Buerger’s disease vs. Atherosclerosis obliterans

14 The cell? Clinically studied: Mobilized PB-MNCs BM-MNCs
CD34+ selected cells BM-MSCs (Bone marrow derived mesenchymal stem cells) Adapted from Fadini et al. Atherosclerosis. 2010;209(1):10-17

15 The way? Intra-arterially or intra-muscular
Combined intra-arterial and intra-muscular Once or repetitive administration Amount of cells needed: Feasibility versus effectiveness Current knowledge points at a strong correlation of effect and amount of cells injected and repetitive infucion seems more effective. No strong evidence whether arterial or intramuscular is more effective.

16 Future perspectives for cell and source
Cell sources: Blood Bone marrow Fat Cord blood Embryonic iPSCs (induced Pluripotent Stem Cells) Cell types: MNC MSC Cultured EPC: Endothelial Colony Forming Cells (ECFCs) Circulating Angiogenic Cells (CACs) Lu et al. Diabetes Res Clin Pract. 2011; [Epub ahead of print]

17 Future perspectives in cell therapy
Progenitor cell dysfunction in cardiovascular diseases Pretreatment of cells could -partly- restore dysfunction: Statins Antioxidants NO-donors PPAR-γ agonists Adapted from Sasaki et al. Proc Natl Acad Sci USA. 2006; 103(39):

18 Harvesting methods Marrow miner:
Claims to harvest more progenitor cells Commercial kits? Be aware: GMP-guidelines Aseptic isolation and culture Knowledge of the product Efficacy still not established Clinical trials are still the way to go!!!

19 Large trials 21 ongoing trials studying stem/bone marrow cell therapy in PAD Significant commercial input Lawall et al. Thromb Haemost. 2010; 103(4):

20 JUVENTAS* Trial (NCT ) * ReJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation bone marrow (100 ml) bone marrow (100 ml) BM-MNC Infusion Placebo versus Storage

21 Juventas-trial Design
Randomized, placebo-controlled, double-blinded clinical trial Objectives Evaluate the effects of repeated intra-arterial infusion of BM-MNC in 110 – 160 CLI patients Study functional characteristics of BM-MNC and relate dysfunction to clinical outcome Currently 100 patients included!!! Highlights Started in September 2006 Design with repeated intra-arterial infusion Over 20 referring centers Group sequential interim analyses for safety and efficacy Coupled basic research

22 Juventas Study Group Steering Group Drs. M. Teraa Dr. R.W. Sprengers
Prof. Dr. M.C. Verhaar Prof. Dr. F.L. Moll Dr. R.E.G. Schutgens Dr. I.C.M. Slaper-Cortenbach Prof. Dr. Y. van der Graaf Prof. Dr. W.P.Th.M. Mali Prof. Dr. P.A. Doevendans Dr. A. de Wit For more information: Data Safety Monitoring Committee Prof. Dr. A. Algra Dr. I. van der Tweel Prof. Dr. T.J. Rabelink The JUVENTAS trial is made possible by grants of: Foundation ‘De Drie Lichten’

23 Question 1 From an embryonic point of view endothelial progenitor cells are closest related to: Neural cells Stromal cells Haematopoietic cells Adipocytes Hepatocytes

24 Answer question 1 From an embryonic point of view endothelial progenitor cells are closest related to haematopoietic cells (answer C). Both the primitive vasculature and haematopoietic cells develop from the blood ilands as a common origin. Endothelial progenitor cells do express both markers expressed on haematopoietic and endothelial cells further underlining their similar ontologic relation.

25 Question 2 The most appropriate way to administer progenitor cells in patients with peripheral arterial disease is: Intramuscular Intraarterially Combination of A and B Still unclear

26 Answer question 2 The most appropriate way to administer progenitor cells in patients with peripheral arterial disease is still unclear (answer D) Most studies conducted so far have studied the intramuscular method to apply cell based therapies. A smaller amount of studies performed intra-arterial infusion. Just one study analyzed a combination of both administration routes. Based on current evidence there seems no clear difference of the administration route applied. Intramuscular administration seemed to perform somewhat better, this was not significant however and needs to be confirmed in controlled studies. Fadini, Agostini, Avagaro. Atherosclerosis 2010; 209: 10-17

27 Question 3 Based on current literature clinical effects of cell therapy is not known to be influenced by: Cell source Number of cells infused Underlying cause of limb ischemia Sex

28 Answer question 3 Based on current literature clinical effects of cell therapy is not known to be influenced by sex (answer D). Clinical effects (ABI, tcPO2) have been shown to be somewhat better in bone marrow derived cells and probably even better in bone marrow derived mesenchymal stem cells. Effects of cell based therapies have almost unequivocally been better with increasing amount of cells administered (mainly number of CD34+-cells). Moreover, ther underlying condition causing the critical limb ischemia clearly plays a role in the effects observed after cell therapy. Patients suffering from atherosclerosis obliterans have shown to be respond better than patients with thromboangitis obliterans. Sex has not yet been shown to influence effects observed after cell therapy. Lu, Chen, Liang et al. Diabetes Res Clin Pract 2011; Epub ahead of print Fadini, Agostini, Avagaro. Atherosclerosis 2010; 209: 10-17 Idei, Soga, Hata et al. Circ Cardiovasc Interv. 2011; 4: 15-25

29 Question 4 What’s true about cell based therapies in peripheral arterial disease: Cell therapy is widely accepted as a conventional therapy Its effects on clinical relevant end points still need to be confirmed Malignant transformation is a serious and common reported problem in cell therapy Growth factor therapies seem equally effective

30 Answer question 4 What’s true about cell based therapies in peripheral arterial disease: “Its effects on clinical relevant end points still need to be confirmed.” (answer B) Cell based therapies have generally shown to improve surrogate end points, such as ABI and tcPO2. Pain free walking distance, ulcer healing and amputation-free survival have also been reported to improve. Most studies conducted were small non-controlled studies and therefore not designed or underpowered to draw definitive conclusions on clinical relevant end points. Fadini, Agostini, Avagaro. Atherosclerosis 2010; 209: 10-17 Sprengers, Moll, Verhaar. Eur J Vasc Endovasc Surg 2010; 39: S38-43


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