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Update in stem cell therapy for cardiovascular diseasesGeorge S. Kobinia M.D.

BM-derived Mononuclear Cells Therapy for Cardiovascular DiseasesWadi El Neel & Suez Canal Authority Hazem Khamis,MD,FACCOctober 6th University

Cardiac disease is still the primary cause of mortality in the wold1.

In the absence of effective endogenous or drug induced repair mechanisms following cardiac injury, cell-based therapies have rapidly emerged as potential novel therapies to treat myocardial failure.1. http://www.who.int/mediacentre/factsheets

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Cellular mechanism (Plasticity)

Paracrine effect (Plasma is important adjuvant)

Secretomes (released after cell death)Mechanisms of action231

BONE MARROW STEM CELLS develop CARDIAC TISSUECD34+ and CD133+ cells.Have more secrete factors.1,2Improved perfusion is CD34+ dose dependent3.

1. Kawamoto A, et al. CD34- positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation. 2006;114:21632169. (Figure) 2. Iwasaki H, et al. Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction. Circulation. 2006;113:13111325. 3. Quyyumi AA, et al. CD34(+) cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent. Am Heart J. 2011;161:98105.1

MNCs from healty volunteers transplanted intracardialy to rats after MI.

Figure. ah, The cardiomyogenic differentiation was identified only in the CD34+ cell group. Representative double immunohistochemistry for human nuclear angigen (HNA) (red) and cardiac troponin I (green) in phosphate buffer saline (PBS) (a, e), low dosis mononuclear cells (loMNC )(b, f), high dosis mononuclear cells (hiMNC) (c, g), and CD34+ cell (d, h) groups. Blue fluorescence demonstrates 46-diamidino-2-phenylindole (DAPI) for nuclear staining. ad, 10; eh, 40;Arrows indicate nuclei of cardiomyocytes expressing HNA (purple, double positive for HNA and DAPI), which indicates differentiation of transplanted human cells into cardiomyocytes.. Figure i-p, . The vasculogenic differentiation was abundantly detected in the CD34+ cell group and rarely in the high mononuclear cells (hiMNC) group but not in the low mononuclear cells (loMNC) and phosphate buffer saline (PBS) groups. Representative double immunostaining for HNA (green) and Von Willenbrand factor (vWF) (red) in the PBS (i, m), loMNC (j, n), hiMNC (k, o), and CD34+ cell (l, p) groups. Blue fluorescence demonstrates 46-diamidino-2-phenylindole (DAPI) for nuclear staining. il, 10; mp, 40;Arrows show nuclei of endothelial cells expressing HNA (pale green, double positive for HNA and DAPI), which indicates differentiation of transplanted human cells into endothelial cells5

PLASMA CytokinesIncreasing evidence suggesting that the cardiovascular beneficial effects of stem cell therapy are largely due to the actions of trophic factors or paracrine mediators1,2,3.

While various single growth factor therapeutic regimens have been attempted for FGF, HGF, IGF, and VEGF, with encouraging results4,5,6,7,the MSC therapy is unique in its engagement of functionally synergistic and redundant trophic factors8,9, that may be required for the activation of the endogenous stem cell repair mechanism and a more sustained therapeutic effect.1. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS, Dzau VJ. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20: 661669, 2006. 2. Tang YL, Zhao Q, Qin X, Shen L, Cheng L, Ge J, Phillips MI. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg 80: 229236, 2005. 3. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289: F31F42, 2005. 4. Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, Ashare AB, Lathi K, Isner JM. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 98: 28002804, 1998. 5. Nakamura T, Matsumoto K, Mizuno S, Sawa Y, Matsuda H, Nakamura T. Hepatocyte growth factor prevents tissue fibrosis, remodeling, and dysfunction in cardiomyopathic hamster hearts. Am J Physiol Heart Circ Physiol 288: H2131H2139, 2005. 6. Serose A, Prudhon B, Salmon A, Doyennette MA, Fiszman MY, Fromes Y. Administration of insulin-like growth factor-1 (IGF-1) improves both structure and function of delta-sarcoglycan deficient cardiac muscle in the hamster. Basic Res Cardiol 100: 161170, 2005. 7. Suzuki G, Lee TC, Fallavollita JA, Canty JM Jr. Adenoviral gene transfer of FGF-5 to hibernating myocardium improves function and stimulates myocytes to hypertrophy and reenter the cell cycle. Circ Res 96: 767775, 2005. 8. Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, Wecker A, Jeong JO, Curry C, Qin G, Yoon YS. Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart. J Exp Med 204: 32573269, 2007. 9. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 103: 12041219, 2008 2

FGF FibroblastHGF HepatociteIGF - Insuline6

Aposec (Secretomes)

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VIDEO7

protocolBM aspiration from the posterior iliac crest.Processing of the BM with an appropriate machine.Coronary angiography / Cannulation of the left and right ostium (ima).Injection of mononuclear cells concentrate in both ostia. (According to BSA).Injection of bm-derived plasma (According to bsa).

INTRACARDIAC INFUSION

RESULTS OF VOLUMES (Linear regression models)White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987 Jul 1;76(1):4451.Patients who died (right) had a significantly steeper slope than those who survived (left)

Patients before the treatment (right) had a significantly steeper slope than those after treatment (left).

Frank-Starling curve

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NYHARESULTSOne class overall improvement

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Khan AR, Farid TA, Pathan A, Tripathi A, Ghafghazi S, Wysoczynski M, et al. Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical Therapy A Systematic Review and Meta-Analysis. Circ Res. 2016 Mar 18;118(6):98493.

Discussion / Between day 1 to 14 should not be studied anymore.

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CONCLUSIONSMore than 10 years since the first cardiovascular treatment with stem cells.

Supporting METHA-ANALYSIS:

Time for Phase III and IV GOOD DESIGNED study.

FUTURE:

Acute: THE POINT-OF-CARE method makes a unique possibility to treat patients in the first 24h. With stem cells and plasma with low cost and high yield and possible reversal of the ongoing infraction. (NOT FROM 24h to 7 days).

Doses

Compare to other therapies.

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Immediately after processing 20cc of MSCs were injected into the main coronary artery (CA) and LCA via , immediately after the insertion of the catheter to the stenosed left coronary ostium (LCO) malignant arrhythmias started, infusion of SC was completed in order to achieve the presume positive effect for the heart.

Cardiac massage for 5 minutes and intubation was performed together with intracoronary infusion of cc adrenaline, electrical activity re-started 2 minutes after the onset of resuscitation.

A repeat coronary angiography at the end of the procedure show dilated coronary arteries, blood pressure and cardiac output recover was surprisingly fast and he could be extubated right in the angiography table.

He was transferred to the coronary care unit (CCU) without mechanical ventilation. The urine output started immediately resulted in 2.3cc per liter in the first 24 hours, extremely improved compared to the pre-operation low urine output without anatomical reconstruction of the coronary anatomy performed. Furthermore despite the long cardiac arrest all the cardiac enzymes were in normal range next morning.

IS OUR BODY MADE OF DRUGS OR CELLS?FDA control over your stem cells