risk assessment of cell doping in sports · 2019-12-20 · risk assessment of cell doping in sports...
TRANSCRIPT
![Page 1: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/1.jpg)
Risk Assessment of Cell Doping in Sports
Shiley Center for Orthopaedic Research & Education
Scripps Clinic
Gene & Cell Doping Symposium, Beijing, June 2013
Darryl D. D’Lima, MD, PhD Director Orthopaedic Research
![Page 2: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/2.jpg)
OUTLINE
• Stem Cell Biology Overview • Cell Therapy for Tendon • Cell Therapy for Muscle • Clinical Trials • Safety Issues • Potential for Doping
![Page 3: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/3.jpg)
Stem Cells Biology
• Function • Source
![Page 4: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/4.jpg)
Function
Function Tissue Generated Examples
Totipotent TE + germ layers Fertilized egg
Pluripotent All germ layers Embryonic stem cell
Multipotent Single germ layer Mesenchymal stem cell
Unipotent Committed Progenitor Osteoblast, Myoblast
Cancer Stem Cell Tumor initiating AML, Breast CA, …
![Page 5: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/5.jpg)
Source
• Embryonic stem cells • Adult stem cells • Gestational • Induced pluripotent cells
![Page 6: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/6.jpg)
• Inner cell mass • Pluripotent • Ethical issues
Embryonic Stem Cells
![Page 7: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/7.jpg)
Adult Stem Cells
• Mesenchymal stem cells • Tissue specific stem cells
– Neuronal – Cardiac – Skeletal Muscle
• Perivascular stem cells • Gestational
![Page 8: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/8.jpg)
Mesenchymal Stem Cells
Caplan A, Tiss Eng 2005
![Page 9: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/9.jpg)
Source – Bone marrow – Blood – Umbilical cord – Synovium – Adipose tissue – Lung – Fetal liver – Dental pulp & deciduous teeth – …
Friedenstein, J Embryol Exp Morphol, 1966
![Page 10: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/10.jpg)
Mesenchymal Stem Cells
• Self Renewal • Differentiation Potential
– Bone – Cartilage – Fat – Muscle – Neuron – Hepatocyte
Friedenstein, J Embryol Exp Morphol, 1966
![Page 11: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/11.jpg)
Mesenchymal Stem Cells
• Immunomodulation – No MHC class II antigens – Disrupt NK, CD8+, CD4+, dendritic cell
function – Anti-inflammatory
• IL-10 • Prostaglandins
Ryan JM, J Inflam 2005
![Page 12: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/12.jpg)
Function
• MSC – VEGF, bFGF, HGF, IGF-1, TGF-β,… – IL-6, IL-10, TNF-α, PGE – Angiogenesis – Inhibit apoptosis & inflammation – Immunoregulation
![Page 13: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/13.jpg)
Mesenchymal Stem Cells • Paracrine tissue regeneration
– Cell survival – Cell proliferation – Angiogenesis
• Osteogenesis Imperfecta – Allogeneic MSC – Clinical improvement – MSC in vivo <2%
Horwitz EM, PNAS 2002
![Page 14: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/14.jpg)
Applications
• MSC – Systemic/Local - homing – Vehicle for gene therapy – Osteogenesis imperfecta – Breast CA (Interferonβ) – Glioma (TNFα - Apoptosis)
![Page 15: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/15.jpg)
Tissue Specific Stem Cells
• Neuronal stem cells – Neurons, astrocytes, oligodendrocytes
• Cardiac stem cells • Muscle stem cells • Perivascular stem cells
![Page 16: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/16.jpg)
Gestational
• Placental • Cord blood • Wharton’s jelly • Amniotic fluid • Amnion, chorion
![Page 17: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/17.jpg)
Induced Pluripotent Stem Cells
Oct4, Sox2, Klf4, c-myc Oct4, Sox2, Nanog, Lin28
Yamanaka, 2006, 2007 Thompson, 2007
![Page 18: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/18.jpg)
Lowry WE & Plath K, Nature Biotech 2008
Induced Pluripotent Stem Cells
![Page 19: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/19.jpg)
Gonzalez et al, Nature Reviews 2011
Induced Pluripotent Stem Cells
• OCT4 single factor • Small molecules
![Page 20: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/20.jpg)
Therapeutic Potential
• Rapid “unlimited” proliferation • Differentiation • Ready source
![Page 21: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/21.jpg)
Musculoskeletal Therapy
• Bone • Cartilage • Tendon/Ligament • Muscles
![Page 22: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/22.jpg)
Tendon & Ligament
• 32 Million injuries US annually • Young: athletic/sports • Elderly: attenuated tissue • Acute traumatic • Chronic repetitive
![Page 23: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/23.jpg)
Tendon & Ligament
• Collagen I (strength) • Collagen III (crosslinks, repair) • Tenoblasts (progenitors) • Tenocytes
![Page 24: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/24.jpg)
Tendon Injury
• >4% Strain microscopic failure • >8% macroscopic failure/rupture
![Page 25: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/25.jpg)
Acute Tendon Injury
• Surgical Repair • Immobilization
• Chronic Rupture • Tendon defect • Autologous graft
![Page 26: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/26.jpg)
Chronic Tendon Injury
• Tendinopathy – Tendinosis – Tendinitis
Maffulli N, Arthroscopy 1998
![Page 27: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/27.jpg)
Chronic Tendon Injury
• Growth Factors – FGF2 – TGF-β – IGF-1 – VEGF – PDGF
![Page 28: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/28.jpg)
Chronic Tendon Injury
• Tissue Engineered • Scaffolds
– Natural (collagen, chitosan, silk) – Synthetic (PLA, PLGA)
• Cells • Platelet-Rich Plasma (PRP)
![Page 29: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/29.jpg)
Chronic Tendon Injury
• Platelet-Rich Plasma (PRP) • Platelets + GF = initial inflammatory
response • ~6000 PubMed reports • Not on WADA prohibited list
![Page 30: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/30.jpg)
Chronic Tendon Injury
• MSC Therapy – Growth factors – Cell survival – Proliferation of endogenous
connective tissue cells – Activate tissue progenitors – Angiogenesis
![Page 31: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/31.jpg)
Chronic Tendon Injury
• Cell Therapy – Allogeneic MSC + fibrin – Achilles tendon (rabbit) – Histological – Biomechanical
Chong AKS, J Bone Joint Surg-A 2007
![Page 32: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/32.jpg)
Chronic Tendon Injury
• ~2,000 Horses • Autologous MSC • Intratendinous Injections
www.vetcell.com
![Page 33: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/33.jpg)
Chronic Tendon Injury
• Human • Autologous skin-derived tenocytes • Refractory patellar tendinopathy
![Page 34: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/34.jpg)
Chronic Tendon Injury
• Human • Allogeneic MSC • Achilles tendon
Clinical Trial, Mark Young, Australia
![Page 35: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/35.jpg)
Muscle
• Athletic Injuries • 35-45% → Muscle Damage
Andia I, Expert Opin Biol Ther 2011
![Page 36: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/36.jpg)
Muscle
• Satellite cells – canonical muscle stem cell
• Numbers == adolescence • Functional decline in aging
– Fibrosis rather than regeneration
![Page 37: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/37.jpg)
• Division • Progenitor (myoblast) • Skeletal muscle cell
Muscle
![Page 38: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/38.jpg)
Cell Therapy
• MTT: Myoblast Transplant Therapy – Poor cell survival – Immune rejection
• Combination Therapy – Myoblast + Growth Factors (bFGF, HGF)
Tedesco FS, J Clin Invest 2010
![Page 39: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/39.jpg)
Cell Therapy
• MSC • Intramuscular Injection • Reduced inflammation • Activate host progenitor cells
![Page 40: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/40.jpg)
Cell Therapy
• Muscle-derived stem cells • Slowly adhering • High level of engraftment • Angiogenic • Clinical trials urinary incontinence
Tedesco FS, J Clin Invest 2010
![Page 41: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/41.jpg)
Cell Therapy
• Myo-endothelial stem cells • Muscle-derived progenitor cell type • Higher survival rate • Superior muscle regeneration
Zheng B, Nat Biotechnol 2007
![Page 42: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/42.jpg)
230 Clinical Trial Registered with FDA (2012)
73%
20%
7%
Clinical Trials
Academia
Industry
Industry + Academia
![Page 43: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/43.jpg)
230 Clinical Trial Registered with FDA (2012)
16%
40% 24%
2%
5% 13%
Clinical Trials
Phase I
Phase I/II
Phase II
Phase II/III
Phase III
Unknown
![Page 44: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/44.jpg)
Pluripotent Stem Cells
• ESC • Spinal Cord Injury (Geron) Frantz S, Nat Biotechnol 2012
• Macular degeneration (ACT) Schwartz, Lancet 2012
![Page 45: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/45.jpg)
Pluripotent Stem Cells
• ESC • Inefficient differentiation • Immunogenicity • Survival
• iPSC – Disease in a dish – Drug screening
![Page 46: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/46.jpg)
Cardiac
• >100 Clinical trials • MSC • Myocardial stem cells • Hematopoietic stem cells • Skeletal Myoblasts • Wharton’s jelly
![Page 47: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/47.jpg)
Point of Care
• Cytori – Celution – PureGraft
![Page 48: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/48.jpg)
Risks of Stem Cell Therapy
![Page 49: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/49.jpg)
Dangers
• Teratoma formation • Immune rejection • Homing • Instability • cGMP: unregulated use?
![Page 50: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/50.jpg)
Teratomas
• Teratomas – IM (12.5%) – SC (25% → 100% with Matrigel) – Intra testicular (60%) – Below kidney capsule (100%)
![Page 51: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/51.jpg)
Immune Rejection
• Loss of graft • Adverse response to
immunosuppression • HLA-matching?
![Page 52: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/52.jpg)
Systemic Migration
• Systemic migration – Hypoxia – Tissue damage
• Systemic allogeneic MSC – No adverse effects – Immunomodulatory effects
![Page 53: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/53.jpg)
Transformation
• Chromosomal abnormalities – HUES1, H1, H9, BG01, HES-1, WA15 – Recurrent gain: 12, 17, X
• Similar to tumors – Testicular tumors – HSRs – iPSC instability
![Page 54: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/54.jpg)
Safety of Adult MSC
• Culture-expanded mesenchymal stem cells Re-injected into peripheral joints (n=213) or into intervertebral discs (n=13)
• No neoplastic complications were detected at any stem cell re-implantation site (MRI)
Centeno CJ, Curr Stem Cell Res Ther 2010
![Page 55: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/55.jpg)
DOPING
![Page 56: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/56.jpg)
Stem Cells & the Athlete
ESPN The Magazine Oct 2011
![Page 57: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/57.jpg)
NFL NBA MLB
![Page 58: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/58.jpg)
Stem Cell Therapy Clinics
![Page 59: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/59.jpg)
Stem Cells & the Athlete
Bartolo Colon – Shoulder & Elbow – Dr. Sergio Guzman – 4% of future earnings
Kobe Bryant – Knee injection
Peyton Manning – Cervical spine – Neuro
LaRon Landry – Achilles Tendon
![Page 60: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/60.jpg)
Amniomatrix
• AmnioMatrix • Cryopreserved human amniotic tissue • Contains living cells • Claim that amniotic cells are not stem cells
![Page 61: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/61.jpg)
Performance Enhancing
• Indirect cell doping: – Stem cells secrete “naturally” occurring
performance enhancing proteins • Mechanogrowth factor • Released naturally
– muscle stretching and exercise
• Rapid increases in muscle mass and strength • Mechanogrowth factor is on WADA's prohibited list • Illegal without a prescription
![Page 62: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/62.jpg)
Performance Enhancing
• Indirect – Overtraining and treating repair or
regeneration with cell therapy – Analogous to local anesthetic injection or
corticosteroids
![Page 63: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/63.jpg)
Indirect Cell Doping
Supplements to stimulate endogenous stem cells
![Page 64: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/64.jpg)
“The Stemtech HealthSciences, Inc product ingredient list is found on the product labels. After review of the WADA (World Anti-Doping Association) banned substance list, to the best of our knowledge Stemtech products do not contain ingredients that are on the banned list. We encourage all athletes subject to anti-doping testing to become fully informed of all products that they consume as well as thoroughly know and understand their organization’s banned substance regulations”
![Page 65: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/65.jpg)
![Page 66: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/66.jpg)
StemEnhance
Double Blind Placebo Controlled Cross Over Study
![Page 67: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/67.jpg)
StemSport Advance • Aphanizomenon flos-aquae Concentrate • Gotu Kola Extract • Cordyceps sinensis • D-Ribose • Indian Gooseberry Extract • Enzyme Blend • Grape Pomace Extract • Undaria pinnatifida Extract • Turmeric Extract • Lemon Fruit Extract • Blackcurrant Extract
![Page 68: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/68.jpg)
StemSport Advance
• Aphanizomenon flos-aquae Concentrate
Mobilization of human CD34+ CD133+ and CD34+ CD133(-) stem cells in vivo by consumption of an extract from Aphanizomenon flos-aquae
Jensen GS, Cardiovasc Revasc Med. 2007
![Page 69: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/69.jpg)
StemSport Advance
• Fucoidan, galactofucan sulfate (a putative hematopoietic progenitor stem cells mobilizing agent)
Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells.
Irhimeh MR, Exp Hematol. 2007
![Page 70: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/70.jpg)
Performance Enhancement
Abuse
Detection
Science progresses to fill an unmet need
Humans will find a way to manipulate advances for their own gain
![Page 71: Risk Assessment of Cell Doping in Sports · 2019-12-20 · Risk Assessment of Cell Doping in Sports Shiley Center for Orthopaedic Research & Education Scripps Clinic Gene & Cell Doping](https://reader033.vdocuments.net/reader033/viewer/2022060214/5f05956f7e708231d413af38/html5/thumbnails/71.jpg)
Risk Assessment of Cell Doping in Sports
Shiley Center for Orthopaedic Research & Education
Scripps Clinic
Gene & Cell Doping Symposium, Beijing, June 2013
Darryl D. D’Lima, MD, PhD Director Orthopaedic Research