Organised by: Co-Sponsored: Malaysian Healthy Ageing Society - 0 - - 0 -
Overview of Stem Cell Therapy Chin Sze Piaw MBBS MRCP FNHAM Consultant Cardiologist, Mawar Medical Centre Visiting Cardiologist, PPUKM Clinical and Research Advisor, Cytopeutics - 1 - - 1 -
Stem Cell Potential - 2 - - 2 -
Defining Stem Cells Stem cells are cells that can self-replicate and differentiate into other specialized cells - 3 - - 3 -
What is True Stem Cell? Embryonic stem cell in first 14 days of life Fetal stem cell divides along 3 germ layers Unethical Banned Causes Cancer - 4 - - 4 -
Embryonic Stem Cells Can Cause Cancer - 5 - - 5 -
Stem cells exist in adults to elicit daily repair The human body recycles itself every 20 years - 6 - - 6 -
Adult stem cells reside in bone marrow Bone marrow transplant established for 30 years Bone marrow transplant is essentially haematopoeitic stem cell (HSC) treatment - 7 - - 7 -
BMSC for non-haematopoeitic diseases? - 8 - - 8 -
Mesenchymal Stem/Stromal Cell (MSC) Differentiates naturally into: • Adipose Cells • Osteoblasts • Cartilage • Cardiac Muscle • Smooth Muscle • Skeletal Muscle Transdifferentiates into: • Hepatocytes • Neurons • Insulin Producing Cells • Renal Mesenchyme Cells - 10 - - 10 -
Differing actions of MSC and PBSC/HSC HSC/PBSC destroys bone; MSC builds - 11 - - 11 -
MSC is present in minute numbers but may be rapidly expanded - 12 - - 12 -
MSC Regenerates New Joint Cartilage MSC-derived cartilage cells staining for Type II Collagen and still retaining capacity for replication (arrows) Choong, Cheong et al, Cytotherapy 2007 - 13 - - 13 -
MSC Regenerates New Joint Cartilage HA Only MSC-HA Saline 6 wk 12 wk Lee et al, Stem Cells 2007 - 14 - - 14 -
MSC Regenerates Hyaline Cartilage MSC-HA HA Only Saline - 15 - - 15 -
MSC can be changed into osteoblast Wong et al 2008, Pathology - 16 - - 16 -
MSC fuses with Damaged Heart Muscle MSC engrafts and fuses with damaged heart muscle cells MSC for Cardiac Muscle - 18 - - 18 -
MSC Repairs Damaged Heart Muscle MSC replaces disorganized scar tissue in the heart with new cardiomyocyte. Laflamme 2007 - 20 - - 20 -
MSC Forms New Blood Vessels MSC differentiates into vascular smooth muscle cells for arteriolar formation (“Not just capillary proliferation”) - 23 - - 23 -
MSC Forms New Blood Vessels MSC differentiates into vascular smooth muscle cells for artieriolar formation - 24 - - 24 -
MSC forms the building blocks for musculoskeletal and supporting structures - 25 - - 25 -
M S C Transdifferentiation - Neuron Induction Choong, Mok, Cheong, Cytotherapy 2010 - 26 - - 26 -
Functional neurons with neurotransmitter expression Choong, Mok, Cheong, Cytotherapy 2010 - 27 - - 27 -
IV M S C - Mechanisms of Actions in Stroke Angiogenesis Engraftment Reduced Scarring Neuron cell regeneration - 28 - - 28 -
MSC hastens recovery from acute renal injury in a mouse model Wong, Cheong Pathology 2008 - 29 - - 29 -
MSC Cell clusters stain crimson red with dilthizone (for insulin expression) Wong, Chin 2010 - 30 - - 30 -
TEM confirms increasing secretory granules in induced MSC Wong, Chin 2010 - 31 - - 31 -
M S C For Diabetes Induced MSC produces insulin in response to different concentrations of glucose stimulation Insulin Production by induced IPC upon various glucose stimulation Insulin Concentration (microIU/mL) 60 48.2 50 40 30 20 13.63 10 3.43 2.67 2.8 2.1 0 5.56 16.7 25 Glucose Stimulation (mMol) Wong, Chin 2010 Uninduced MSC Induced IPC - 32 - - 32 -
Proven that our MSC can be differentiated into specialized cell types Osteoblast Chondro- Insulin (beta blast islet) cell (& NP Cell) MSC Neuron Adipocyte Cardiac Arteriole Muscle - 33 - - 33 -
We Have Successfully Produced True MSC - 34 - - 34 -
Using Proprietary, Animal-free Medium for rapid expansion,… 3 days 6 days 12 days (MSC reached confluence) 9 days - 35 - - 35 -
Safe for Clinical Applications We are able to culture 500 million high quality MSC from just 10- 20 ml BMA within a month for clinical treatment - 36 - - 36 -
We ensure all cells retain identical characteristics as original - 37 - - 37 -
All processing in a GMP compliant lab Large clean room 100 facility Large clean room class 100 for (future expansion) Laminar air flow Individualized incubators Layout (Goods flow and Human flow) according to GMP ISO 15189 for hematology testing - 38 - - 38 -
Product Traceability and Safety during storage and transportation - 39 - - 39 -
On-site Final Preparation - 40 - - 40 -
ISO 15189, CLEAN ROOM CLASS 100, GMP COMPLIANCE BY BPFK - 42 - - 42 -
Potential mesenchymal stem cell applications - 44 - - 44 -
Bone Marrow Cells Are Proven Safe Meta-analysis of 999 heart failure patients Autologous Bone-Marrow Derived Stem Cells Are Safe - 46 - - 46 -
From Atherosclerosis to MI and Heart Failure Endothelial Progenitor Smoking Diabetes HPT Lipid Cell (EPC) also Inflammation dysfunctional in cardiovascular patient. Endothelial Cell Death Damage & EPC Therefore unable to Dysfunction repair endothelial cell damage, leading to atherosclerosis Heart Failure & Atherosclerosis & Cardiac Arrest Atherothrombosis Scar tissue is easily stretched, does not return to shape. Gives Dilatation & MI/Heart Attack Electrical rise to progressive instability heart dilatation and also electrical Scarring arrhythmias - 47 - - 47 -
Methodology Phase IIb Trial. (NMRR Research ID No: 582) 20 patients screened between 2008-2009 • 8 patients had significant viable myocardium: sent for revascularization initially • 2 with BBB: sent for consideration of bivent pacing (20) Symptomatic (NYHA II-IV) • 5 with ischemic cardiomyopathy Severe Dilated Cardiomyopathy (LVEF < 35%) deemed unlikely to benefit from revascularization alone Suitable for/ likely to benefit from revascularization alone • 2 had previous and patent vessels • 3 non-ischemic cardiomopathy Suitable for bivent pacing (10) No. (10) Yes. Assignment Plan for revasc (8) or bivent pacing (2) first (5) Multivessel disease (5) Patent vessels (2) /Non-ischemic (3) Intracoronary MSC injection Intramyocardial MSC with concurrent CABG alone - 50 - - 50 -
LV Ejection Fraction Baseline 6 weeks 3 months 6 months 12 months Total 26.5 + 6.7 38.6 + 12.8^ 44.5 + 12.3* 47.4 + 7.2* 58.7 + 12.6^ Intracoronary 26.9 + 6.2 33.9 + 6.7 39.6 + 6.3^ 41.7 + 4.1* 47.7 + 2.8^ Intramyocardial 26.1 + 7.8 43.4 + 16.3^ 49.5 + 7.9^ 53.1 + 4.4^ 69.6 + 5.7^ Early rapid recovery – Paracrine effect Late sustained recovery - Regeneration P values when compared to baseline ^ P less than 0.05 * P less than 0.01 Accepted Eur Heart J 2010 - 52 - - 52 -
MRI viability study – Intramyocardial injection Baseline 12 months Gadolinium delayed enhanced constrast Resolution of scar and increased MRI shows concentric and full thickness myocardial thickness with new scarring (white area) myocardium (grey and black areas) Accepted Eur Heart J 2010 - 54 - - 54 -
Findings corroborated by independent research group - 55 - - 55 -
REPAIR-AMI: 1 year follow-up 35 30 25 20 15 10 5 0 Death MI HF Hosp PCI Stroke Arrhythmias/Syncope Placebo BMC Schachinger et al 2006 - 56 - - 56 -
Patient Population • 15 patients (Male 4; Female 11) • Mean age 68 + 12.7 years • Severe OA • Significant varus/valgus deformity • Pain and reduced mobility on NSAIDs or COX2 • Failed multiple hylauronic injections • No change or worsening OKQ * in previous 6 months * Oxford Knee Qustionaire - 57 - - 57 -
MSC as a Single Injection in Severe refractory osteoarthritis Chondrocell in a 3D biodegradable scaffold 2-3 mLs injected into knee capsule containing 1-2 million cells per kg body weight - 59 - - 59 -
Change in Functional Score from baseline Prior to Tx 6 mths 12 mths 15 R R L L 10 6 10 6 5 10 Major Improvement 6 R L Mild Improvement 3 2 0 No Change -1 -1 -1 -2 -3 -5 -3 Worse -4 -5 -5 -13 -10 -10 Comparing OKQ scores to baseline -15 -4 or less: Worse -3 to 3: No change 4 to 9: mild improvement 10 or more: major improvement - 62 - - 62 -
MRI independantly reported • Increased in cartilage thickness by 40% (noted in 40%) • Resolution of subchondral cysts (noted in further 10%) • Reduction in effusion (noted in further 10%) Das Gupta, et al (Accepted Int J Rheuamtic Dis 2010) - 63 - - 63 -
MSC Effective for OA in a FDA Multi-Centre Clinical Trial To assess the safety of an injection of stem cells into the joint capsule and to gain preliminary efficacy data on the ability of MSC to impact symptomatic improvement, tissue regeneration and the development of osteoarthritis Method : Randomized, prospective, double blind study at 7 leading sports centre in the US, 55 Patients with moderate-severe OA and torn meniscus 1 WEEK Single injection Single injection Multiple injection LD 50 million MSC HD 150 million MSC HA In biodegradable matrix In biodegradable matrix - 64 - - 64 -
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