Presentation on theme: "Prof. dr. M.C. Verhaar, MD PhD 2"— Presentation transcript:
1 Prof. dr. M.C. Verhaar, MD PhD 2 Stem and Progenitor Cell Therapy in Peripheral Arterial Disease Current knowledge and controversiesDrs. M. Teraa, MD 1,2Prof. dr. M.C. Verhaar, MD PhD 2Prof. dr. F.L. Moll, MD PhD 11 Department of Vascular Surgery, University Medical Center Utrecht, The Netherlands2 Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands
2 Backgrounds Critical Limb Ischemia (CLI) Rest pain or tissue necrosisindividuals per million persons per yearImportant functional implicationsMajor impact on quality of life:Worse than in patients with terminal cancer, chronic kidney or heart diseaseCLI 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 lesionExtent of diseaseExtensive co-morbidityNo effective pharmacological therapyAmputation often remaining optionNew revascularization strategies neededCell therapy is a promising option
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 resultsWhat about cell therapy?
9 Cell therapy – TACT Study (2002) First Clinical trialPilot study (25 patients)BM-MNC vs salineSignificantly improved ABI, TcPO2, rest pain, pain-free walking time at 4 and 24 weeksRandomized trial (22 patients)BM-MNC vs PB-MNCSignificant improvement for BM-MNCAdapted from Tateishi-Yuyama et al. Lancet. 2002;360(9331):427-35
10 Current results on cell therapy in CLI Mainly small non-controlled studiesAdapted from Fadini et al. Atherosclerosis. 2010;209(1):10-17
11 Need for confirmation!!! Large randomized controlled trials More clinical relevant end points:AmputationMortalityQuality of LifeElucidate the black box of cell therapy
13 Which patient will benefit? Young vs. OldDiabetics vs. Non-diabeticsMale vs. FemaleChronic kidney diseaseBMISmokers vs. Non-smokersFontaine III vs. Fontaine IVBuerger’s disease vs. Atherosclerosis obliterans
14 The cell? Clinically studied: Mobilized PB-MNCs BM-MNCs CD34+ selected cellsBM-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-muscularOnce or repetitive administrationAmount of cells needed:Feasibility versus effectivenessCurrent 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:BloodBone marrowFatCord bloodEmbryoniciPSCs (induced Pluripotent Stem Cells)Cell types:MNCMSCCultured 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 diseasesPretreatment of cells could -partly- restore dysfunction:StatinsAntioxidantsNO-donorsPPAR-γ agonistsAdapted from Sasaki et al. Proc Natl Acad Sci USA. 2006; 103(39):
18 Harvesting methods Marrow miner: Claims to harvest more progenitor cellsCommercial kits? Be aware:GMP-guidelinesAseptic isolation and cultureKnowledge of the productEfficacy still not establishedClinical trials are still the way to go!!!
19 Large trials21 ongoing trials studying stem/bone marrow cell therapy in PADSignificant commercial inputLawall et al. Thromb Haemost. 2010; 103(4):
21 Juventas-trial Design Randomized, placebo-controlled, double-blinded clinical trialObjectivesEvaluate the effects of repeated intra-arterial infusion of BM-MNC in 110 – 160 CLI patientsStudy functional characteristics of BM-MNC and relate dysfunction to clinical outcomeCurrently 100 patients included!!!HighlightsStarted in September 2006Design with repeated intra-arterial infusionOver 20 referring centersGroup sequential interim analyses for safety and efficacyCoupled basic research
22 Juventas Study Group Steering Group Drs. M. Teraa Dr. R.W. Sprengers Prof. Dr. M.C. VerhaarProf. Dr. F.L. MollDr. R.E.G. SchutgensDr. I.C.M. Slaper-CortenbachProf. Dr. Y. van der GraafProf. Dr. W.P.Th.M. MaliProf. Dr. P.A. DoevendansDr. A. de WitFor more information:Data Safety Monitoring CommitteeProf. Dr. A. AlgraDr. I. van der TweelProf. Dr. T.J. RabelinkThe JUVENTAS trial is madepossible by grants of:Foundation ‘De Drie Lichten’
23 Question 1From an embryonic point of view endothelial progenitor cells are closest related to:Neural cellsStromal cellsHaematopoietic cellsAdipocytesHepatocytes
24 Answer question 1From 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 2The most appropriate way to administer progenitor cells in patients with peripheral arterial disease is:IntramuscularIntraarteriallyCombination of A and BStill unclear
26 Answer question 2The 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 3Based on current literature clinical effects of cell therapy is not known to be influenced by:Cell sourceNumber of cells infusedUnderlying cause of limb ischemiaSex
28 Answer question 3Based 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 printFadini, Agostini, Avagaro. Atherosclerosis 2010; 209: 10-17Idei, Soga, Hata et al. Circ Cardiovasc Interv. 2011; 4: 15-25
29 Question 4What’s true about cell based therapies in peripheral arterial disease:Cell therapy is widely accepted as a conventional therapyIts effects on clinical relevant end points still need to be confirmedMalignant transformation is a serious and common reported problem in cell therapyGrowth factor therapies seem equally effective
30 Answer question 4What’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: 10-17Sprengers, Moll, Verhaar. Eur J Vasc Endovasc Surg 2010; 39: S38-43