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In the name of God

In the name of God. Mesenchymal stem cell therapy in Neonates Shahid Beheshti medical university mofid Children Hospital Bibi shahin shamsian. Mesenchymal cell therapy in Neonates. Introduction.

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In the name of God

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  1. In the name of God Mesenchymal stem cell therapy in Neonates Shahid Beheshti medical university mofid Children Hospital Bibishahinshamsian

  2. Mesenchymal cell therapy in Neonates

  3. Introduction • Despite recent advances in Neonatal Medicine, Neonatal disorders: Bronchopulmonary dysplasia (BPD) Intraventricular (IVH ) in preterm neonates & Hypoxic ischemic Encephalopathy in term neonates :Major causes of Mortality & Morbidities. • Promising preclinical research results suggest: • Stem Cell Therapies represent the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex Multifactorial Etiologies.

  4. Stem cells Cell Therapy & Regenereative Medicine • Stem cells , Naivecells-Specialized cell: • Renewing themselves • Differentiate into multi-lineage cells • Stem cell Classification: • Embryonic Stem Cells (ESCs) • Induced Pluripotent Stem Cells (I-PSCs) • Adult Stem Cells Xin WEI1 .ActaPharmacologicaSinica (2013) 34: 747–754

  5. Embryonic stem cells (ESCs) &Induced pluripotent stem cells (iPSCs) ESCs ESC: Pluripotent stem cells; Inner cell mass of a blastocyst, an early-stage pre- implantation Embryo IPSCs : Adult Somatic Cells :Reprogrammed to an Embryonic Stem Cell-like state by enforced expression of pluri potency transcription factors Risks: Ethical issues & Teratoma potential

  6. Stem cell ClassificationAdult Stem Cells Classification Adult Stem cells • Adult Stem Cells: • Hematopoietic Stem Cells (HSC) • Mesenchymal Stem Cells(MSC) • ….

  7. Mesenchymal stem cell • Non-Haematopoietic • Maintenance of Bone Marrow Homeostasis • Multipotent stem cells • (Osteoblasts, Adipocytes, & Chondroblasts) • Free of both Ethical concerns & Teratoma potential Xin WEI1 .ActaPharmacologicaSinica (2013) 34: 747–754

  8. Definition of an MSC :International Society for Cellular Therapy in 2006 .( 3 criteria) Minimal criteria of Mesenchymal Stem Cells.Korean Journal of Internal Medicine Vol. 28, No. 4, July 2013

  9. Sources MSC • MSCs exist in almost all tissues: • Bone marrow (BM-MSCs) • umbilical cord blood (UCB-MSCs) • Wharton’s jelly • Placenta (P-MSCs) • Amniotic fluid (AF-MSCs) • Adipose tissue (ADSCs) • Exfoliated deciduous teeth Xin WEI1 .ActaPharmacologicaSinica (2013) 34: 747–754 SylwiaBobis. FOLIAHISTOCHEMICA ETCYTOBIOLOGICA Vol. 44, No. 4, 2006 Yonsei. Med J. 2017 Mar 1 ;58(2)266-271Stem cell therapy for neonatal Disorers

  10. Placenta-Derived and Amniotic Fluid-Derived MSCs BM-MSCs have been the“Gold standard,” Fetal sources ;(21.1%) umblical cord blood,placenta UC/UCB-MSCs may be a “platinum standard. Wang et al. Journal of Biomedical Science (2016) 23:76

  11. Gestational tissues, rather than adult tissues, might be a promising source for obtaining exogenous human MSCs for future clinical use in treating neonates with intractable disorders • MSCs (Gestational tissues): • Easy Obtainability • No significant Ethical Concerns • Lower Immunogenicity • Higher Proliferative Capacity • Paracrine Potency > Adult Tissue Mueller et al. Molecular and Cellular Pediatrics (2016) 3:6 YunSilChang.Yonsei Med J 2017 Mar;58(2):266-271

  12. Mode of action of MSCs as cell therapy agents • The Clinical use of MSCs :Biological characteristics • 4 properties of MSCs in clinical uses: • Ability to differentiate into various cell types • Ability to migrate to sites of inflammation when injected intravenously • Ability to secrete multiple bioactive molecules capable of inhibiting inflammation and healing injured cells • Ability to perform immunomodulatory functions while lacking immunogenicity BrunaAmorin •Human Cell (2014) 27:137–150

  13. Mesenchymal Stem Cell Therapy for Pediatric Disease: Perspectives on Success and Potential Improvements • 1980s - Arnold Caplan, MSC-based therapy have As an extremely promising therapy in Adult medicine, and then pediatric • MSCs :Represent a potentially revolutionary therapy for a wide variety of pediatric diseases including Neonates CHRISTOPHER R. NITKIN Mese Ohio, USA STEM CELLS TRANSLATIONAL MEDICINE 2017;5:1–27 w.

  14. The Central Question to MSC therapy • Question is not:“Are MSCs therapeutically effective?” • Rather,it is: “How can we optimize MSC therapy for efficacy While avoiding Adverse Efects?” • Optimize the therapeutic application of MSCs, including in the pediatric population CHRISTOPHER R Nitkin. STEM CELLS TRANSLATIONAL MEDICINE 2017;5:1–27 Cleveland, Ohio, USA

  15. Clinical Trials / MSC • NIH Clinical trial Database- APR 2016 > 500 MSC related clinical trials • > Half (42%) in Immune/ Inflamation mediated disease • Most Evaluation : • Phase 1 or 2( Safety and Efficacy) • small nu phase 3 • Just , 1 phase 4 trial, for Side Effectss after Marketing CHRISTOPHER R Nitkin. STEM CELLS TRANSLATIONAL MEDICINE 2017;5:1–27 Cleveland, Ohio, USA

  16. Clinical phases of mesenchymal stem cells-based therapy. Data from Clinical Trials.gov. Xin WEI1 .ActaPharmacologicaSinica(2013) 34: 747–754

  17. pediatric Diseases/ MSC • Neonates: • Bronchopulmonary Dysplasia( Neonates) • Severe Intraventricular Hemorrhage (IVH) • Hypoxic Ischemic Encephalopathy (HIE) • Periventricularleukomalacia (PVL). • Phase I clinical trials (MSC -Neonates) :BPD, HIE, severe IVH :Safe, Feasible, potentially Efficacious

  18. Stem Cell Therapy for Neonatal Diseases Associated with Preterm BirthAlessandro Borghes. J ClinNeonatol. 2013 Jan-Mar; 2(1): 1–7 • Neonatal Medical Care: Increased survival of VLBW infants, , extends to 22 weeks Gestational Age • Extreme preterm birth : significant morbidity short-term & long-term pulmonary complications • Broncho pulmonary dysplasia- BPD up to 43% of infants , BW< 1500 g • Neurologic : • PeriventricularLeukomalacia (PVL )

  19. Stem Cell Therapy for Neonatal Diseases Associated with Preterm BirthAlessandro Borghes. J ClinNeonatol. 2013 Jan-Mar; 2(1): 1–7 • Mechanisms underlying tissue simplification is still incomplete?? • Directly Damaging of Stem/Progenitor cells, by Combination of Risk factors including : • Oxidative stress- ROS and RNS • Genetic predisposition • Deprivation of maternal/placental molecules

  20. Stem Cell Therapy for Neonatal Diseases Associated with Preterm BirthAlessandro Borghes. J ClinNeonatol. 2013 Jan-Mar; 2(1): 1–7 Common mechanisms of pathogenesis in diverse diseases of prematurity Common mechanisms of pathogenesis in diverse diseases of prematurity

  21. Clinical trial In Neonates • Phase I clinical trial for BPD • Phase I clinical trial for HIE • Phase I clinical trial for IVH Mueller et al. Molecular and Cellular Pediatrics (2016) 3:6 YunSilChang.YonseiMed J 2017 Mar;58(2):266-271 Maria Pierro1Mesenchymal stem cells for the prevention and treatment of b ronchopulmonary dysplasia in preterm infants (Protocol).2015

  22. Chang, et al;Phase I clinical trial for BPD • single intratracheal (IT) transplantation of Allogenic human umbilical cord blood (UCB)-derived MSCs for BPD. • 9 very preterm infants at high risk , BPD mean GA 25 weeks (range: 24–26 weeks) & a mean birth weight of 793 g (range: 630–1030 g) at a mean age of 10 days (range: 7–14 days) after birth. • all on continuous ventilator support with no signs of imminent clinical improvement. • 3 low dose (1×107 cells/kg in 2 mL/kg of saline), 6 high dose (2×107 cells/kg in 4 mL/kg of saline). • MSCs intratracheally in 2 fractions into the left and right lungs via a gavage tube • well tolerate,without any serious adverse effects or doselimiting toxicity up to 84 days • No significant differences in serious adverse effects were observed between the low- and high-dose groups. • Levels of cytokines in tracheal aspirates at day 7 following treatment were significantly reduced, compared with those at baseline. • Furthermore, BPD severity was significantly lower in transplant recipients, compared with the historical gestational age-, birth weight-, and respiratory severity score-matched control group. • A long-term follow-up study and a phase II, double-blind, randomized, controlled trial to assess therapeutic efficacy are underway. YunSilChang.Yonsei Med J 2017 Mar;58(2):266-271

  23. Broncho pulmonary dysplasia/MSC • First Clinical trial of MSCs in neonates for BPD :2014 • PNEUMOSTEM, Allogeneic human UCB-MSC product(expanded exvivo in FBS to passage 6), ,dose-escalation study (1–2 x 107 cells /kg) via Endotracheal tube to 5- 14-day-old extremely preterm neonates -at 27 weeks -or younger. • Ttreated :less severe BPD ,reduced levels of inflammation,and no treatment-related adverse effects Ciprianp.Stem Cell Therapy in Neonatal Disease.2015s CHRISTOPHER R Nitkin. STEM CELLS TRANSLATIONAL MEDICINE 2017;5:1–27 Stem cells for brain repair in neonatal hypoxia–ischemia.L. Chicha

  24. Phase I clinical trial for IVHYonsei Med J 2017 Mar;58(2):266-271 Human UCB-derived MSC transplantation in preterm infants with severe IVH (i.e., grade≥3) Safety & feasibility of a single intraventricular -Allogenic human UCB-derived MSCs within 7 days after detection of severe IVH (grade≥3) under ultrasound guidance in preterm infants. 9 preterm infants - severe IVH, 3 were given a low dose (5×106 cells/kg in 1 mL/kg of saline); 6 infants were given a high dose (1×107 cells/kg in 2 mL/kg of saline. Infants are currently undergoing follow-up care for long-term adverse outcomes and assessment of neurologic health YunSilChang.Yonsei Med J 2017 Mar;58(2):266-271

  25. Phase I clinical trial for HIECotten, et al Autologous UCB cell transplantation in a phase I clinical trial 23 neonates with HIE ,concurrent hypothermia treatment. IV infusion of non-cryopreserved, Autologous, up to four doses of 1– 5×107 cells per dose Feasible & well tolerated. No significant adverse reactions, Cardiopulmonary compromise, or Infections UCB recipients- better 1-year survival rates (74%) than concurrent cooled infants (41%) Randomized, double-blind, controlled clinical trials in the future will be required YunSilChang.Yonsei Med J 2017 Mar;58(2):266-271

  26. PROSPECTS AND CHALLENGES FOR CLINICAL TRANSLATION • CHALLENGES • Right patients: High risk • Right Cells: Auto versus Allo MSC • Right Route: Systemic versus Localized • Right Timing: Early Vs late • Right Dose:??? • Safety of MSC Transplantation( GMP) CHRISTOPHER R Nitkin.STEM CELLS TRANSLATIONAL MEDICINE 2017.5:1–27 YunSilChang.Yonsei Med J 2017 Mar;58(2):266-271

  27. Right Patients • Newborn infants at highest risk for developing intractable diseases • Mortality & Morbidities • Gestational Age • prolonged Respiratory support • Additional clinical predictors and/or Biomarkers

  28. AllO Vs AUTO MSC • Autologous MSC: %32.5 • Allogenic MSC: %50 • MSCs : • Weak expression of MHC class I • Absent MHC class II markers • “Off-the-Shelf ”:Allogeneic product- Healthy Donor ? • BPD trial could be administered within the first few minutes of life or within hours of diagnosis Wang et al. Journal of Biomedical Science (2016) 23:76

  29. Right Route • Local : Intaratheraceal, Intrathecal, Intranasal • systemic: Intraperitoneal -Intravenous • systemic: • Minimally-Invasive • Limitations in crossing the blood brain barrier(BBB) • Retain in other organs, such as the lungs, liver, spleen, and kidneys • 4 to 5,Fold Higher Doses

  30. Right Time • Therapeutic time window for stem cell therapy might be narrow • Further studies will be necessary to clarify this

  31. Right Dose • Factors: • Underlying disease & Severity • Route of Administration. • phase I clinical trial for severe IVH; • No dose limiting toxicity or serious adverse events were observed with either dose.

  32. Good Manufacturing Practice • Safety of MSC transplantation • High-quality • Standardized • Absence of Adverse Effects • MSC exert their therapeutic function by a “Hit and Run” mechanism • Absence of Adverse Effects including Tumorigenicity duo to Absent Engraftment of the transplanted MSCs

  33. Before large-scale translation into the clinical arena ,however factors such as cell source, culture conditions, donor factors, recipient factors, and ex vivo differentiation must be addressed CHRISTOPHER R Nitkin. STEM CELLS TRANSLATIONAL MEDICINE 2017;5:1–27

  34. Conclusion • Energy and attention ;to detail that will optimize the therapeutic application of MSCs in the pediatric population including Neonates • Essential to proceed Step by step rather than haste

  35. Thank You

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