By Justin Klee and Lucy Schultz Stem Cell Therapy for Major Adverse Cardiac Events Following Acute Myocardial Infarction By Justin Klee and Lucy Schultz

Overview Basic Physiology of the Heart About Acute Myocardial Infarction (AMI) Adverse Post-AMI Events Stem Cell Therapy As Treatment How it Works Current Status Conclusion

The Heart Supplies the Body With Blood Responsible for pumping blood through the body About 2,000 gallons of blood/day Four chambers http://biology-forums.com/gallery/3805_30_04_11_1_50_38.jpeg Three Tissue Layers Pericardium - Protection Myocardium - Involuntary smooth muscle Epicardium - Lining http://faculty.stcc.edu/AandP/AP/imagesAP2/heart/heartwall.gif

Acute Myocardial Infarction (AMI) is a Disruption of this Central Process A.K.A. Heart attack Interruption of blood flow to a part of the heart muscle Symptoms: Squeezing pain, heaviness, tightness, or pressure in chest; pain in back, left arm, jaw, or neck; shortness of breath; dizziness; weakness; nausea or vomiting; irregular heartbeat; sweating; feeling of doom For women: heartburn, pain in abdomen, unusual fatigue, clammy skin Risk Factors: Smoking, high fat diet, lack of exercise, being overweight or obese, family history of heart attack, diabetes, high blood pressure, being male or a female who has gone through menopause, stress usually because of coronary artery blockage or arthersclerosis

ST-Elevated Myocardial Infarction (STEMI) is a Severe Subset Coronary artery is completely blocked off by blood clot Heart muscle supplied by affected artery begin to die Results in reduced Left Ventricular Ejection Fraction (LVEF) < 50% Named for elevated ST wave on ECG Target population for AMR-001 therapy Braunwald et al. 2002 20% of AMIs; 160,000 patients/year

Impact on Patients is Large 10 million AMI events each year worldwide 715,000 AMI events each year in the US 20%, or 160,00 AMI patients have a ST-Elevation MI 95% of people hospitalized with a heart attack survive Yet, 1 in 5 MI patients older than 45 will be dead within a year Why?

Heart Function is Impaired After MI Cardiac cell death leads to infarct expansion (scar) Remaining heart muscle unable to compensate for damaged heart tissue Patients at significant risk of adverse effects such as: Congestive heart failure Recurrent MI Arrhythmias Premature death $30,000-$80,000 in medical costs per patient per year 60% of patients; Physiological changes in the heart due to acute loss of myocardium, Myocyte necrosis results in a cascade of biochemical intracellular signaling processes that initiate and modulate reparative changes, Peri-Infarct Zone forms surrounding infarct tissue , Has inadequate blood supply, Works harder to compensate for neighboring, non functioning myocardium, Signals for increased perfusion, Without response, this tissue begins to undergo apoptosis, Expands infarction region Image courtesy of Amorcyte Jagtap et al., 2005

Most Currently Available Treatments are Ineffective Lifestyle changes (exercise, diet, smoking, etc.) Medications Aspirin, nitroglycerin, ACE inhibitors, Beta-blockers, Statins Surgical treatments Coronary Artery Bypass Graft (CABG) Percutaneous Coronary Intervention (PCI) LVEF is improved after PCI by only 3% to 4% Percutaneous coronary intervention only restore heart muscle function to a minor degree Longstanding (up to 3 years and more) improvement of ventricular performance after therapy http://media.npr.org/assets/img/2011/10/28/aspirin-3f9e6740f1d37bd7ba221c74c7009fc6e2ed0534-s6-c10.jpg

Can adult stem cells be administered after a patient has suffered a heart attack to preserve heart muscle that would otherwise die? Milk Genomics Consort

Amorcyte (Neostem) Believes Yes Clinical development-stage cell therapy company Focused on treatments for cardiovascular disease Lead product candidate is AMR-001 Therapy for the preservation of heart muscle function and prevention of major adverse cardiac events following STEMI Granted first US patent for a chemotactic hematopoietic stem cell product, its delivery, as well as cell potency and stability

AMR-001 Stem Cell Therapy is Accessible and Promising Autologous bone marrow CD34+ stem cell product Contain several cell populations able to proliferate, migrate, and differentiate Bone Marrow Stem Cells (BMSC) easily accessed, renewable, autologous source for regenerative cells Image courtesy of Amorcyte Hematopoetic, mesenchymal, endothelial progenitor, and side population cells

Patients Who Have Suffered an AMI Are Eligible for Therapy Previous myocardial infarction with LVEF < 50% Intracoronary stent implant Wall motion abnormality in infarct-related artery myocardium Studies suggest age of infarct less relevant for regenerative potency of BMCs

Therapy Administered During Out-Patient Procedure Adult bone marrow blood aspirated from iliac crest under local anesthesia CD34+/CXR4+ cells harvested Single dose Infused via infarct-related artery 6-11 days following STEMI Conscious sedation and local anesthesia Out-patient procedure in catheterization laboratory Balloon catheter within stent Automatic sorting mechanism to separate nucleated or mononuclear cells from aspirate Images courtesy of Amorcyte

BMSC Therapy Models Natural Response Mechanism Mechanism modeled after natural response Distress signal induced by hypoxia in peri-infarct zone Induces synthesis of SDF-1 and VEGF, which are natural signal to mobilize CD34+ CXCR4+ cells BMSC differentiate into cardiomyocyte-like cells Enhance angiogenesis Improve regional blood flow Enhance angiogenesis Improve regional blood flow Decrease infarction size Improve cardiac function Supply angiogenic ligands and cytokines Supply angioblasts Increase survival of endothelial lineage cells Supply antiapoptotic factors for endothelial cells

Clinical Benefits Found for AMI Patients Threshold dose >10 million cells Increase in ejection fraction by 3-36% (mean 11.4%) Decreased infarct size by 1- 60% (mean 34%) Longstanding (up to 3 years and more) improvement of ventricular performance after therapy Benefits sustained up to 5 year follow-up Large variety of effects may be stem cell-related methods or dependent on different methods of evaluation Strauer, Bodo-Eckehard et al. 2010

Clinical Benefits Found for AMI Patients Schachinger et al., 2011

AMR-001 Clinical Trial Shows Beneficial Results Phase I Clinical Trial Amorcyte 31 patients Results demonstrated that patients receiving 10-15 million cells showed significant improvement in perfusion rates after 3 months Improvement in ejection fraction, end systolic volume, infarct size, and tissue death after 6 months Quyyumi et al., 2011 Image courtesy of Amorcyte

No Complications Yet Found Effective and safe therapy Did not find: Major stem cell-related side effects Procedure-related side effects Tumor formation Progression of coronary artery diseases Cardiac arrhythmias Immunosuppressive therapy necessary Inflammation inflammation assessed by: Assessed through white blood cell count, serum levels of C-reactive protein, and creatine phopshpokinase

AMR-001 is Being Tested in a Larger, Longer Phase II Clinical Trial Current Phase II Clinical Trial To evaluate the potential to improve perfusion, preserve cardiac function, and improve clinical outcomes Placebo controlled, double-blind study Began enrolling patients in January 2012 Intend to enroll 160 patients Patients will initially be followed for 6 months Tracked for 3 years post treatment (80 control, 80 treatment)

AMR-001 Is a Promising Treatment Option AMR-001 and other autologous Bone Marrow Stem Cell therapies are safe and effective procedures able to greatly improve patient outcome after severe heart attack. Great option for patients who have just suffered a heart attack

What's Next? Therapy for Congestive Heart Failure? Other Ischemic Injuries?

References http://www.umm.edu/altmed/articles/myocardial-infarction-000115.htm http://ceaccp.oxfordjournals.org/content/7/3/85.full Quyyumi, Arshed A. et al. CD34+ cell infusion after ST elevation myocardial infarction is associated with improved perfusion and dose dependent. American Heart Journal: 2011. Strauer, Bodo-Eckehard et al. 10 Years of Intracoronary and Intramyocardial Bone MArrow Stem Cell Therapy of the Heart. Journal of American College of Cardiology: 2011. Schachinger, Volker et al. Improved clinical outcome after intracoronary administration of bone- marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the repair AMI trial. European Society of Cardiology: 2006. Sutton, Martin G. et al. Left Ventricular Remodeling AFter Myocardial Infarction: Pathophysiology and Therapy. Circulation: 2000. Kamihata, Hiroshi et al. Implantation of bone marrow mononculear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation: 2001. Kinnaird, T. et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research: 2004. Neostem.com Hare, Joshua et al. A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells After Acute Myocardial Infarction. Journal of American Cardiology: 2009. Mocetti, Tiziano et al. Sustained improvement in left ventricular function after bone marrow-derived cell therapy in pateints with acute ST elevation myocardial infarction. Swiss Medical Weekly: 2012. http://flipper.d.org/app/items/info/3868

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