Neuron Point-Of-Care Stem Cell Therapy by SCT Vienna


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Neuron point-of-care stem cell therapy (N-POCST): Transplantation of autologous bone marrow-derived stem cells for traumatic central nervous system disorders, the future of a new method.
SCT Vienna

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Neuron Point-Of-Care Stem Cell Therapy by SCT Vienna

  1. 1. Neuron point-of-care stem cell therapy (N-POCST): Transplantation of autologous bone marrow-derived stem cells for traumatic central nervous system disorders, the future of a new method.
  2. 2. Situation TRAUMATIC BRAIN INJURY Each year 235 000 persons in US are hospitalized for nonfatal TBI and 50 000 die (Corrigan et al. 2010) The prevalence of US civilian residents living with disability following hospitalization with TBI is 3.2 million (Corrigan et al. 2010). Despite claims to the contrary, no clear decrease in TBI-related mortality or improvement of overall outcome has been observed over the past two decades. (Roozenbeek et al. 2013) Corrigan, J.D., Selassie, A.W., Orman, J.A.L., 2010. The epidemiology of traumatic brain injury. J. Head Trauma Rehabil. 25, 72–80. doi:10.1097/HTR.0b013e3181ccc8b4. Roozenbeek, B., Maas, A.I.R., Menon, D.K., 2013. Changing patterns in the epidemiology of traumatic brain injury. Nat. Rev. Neurol. 9, 231–236. doi:10.1038/nrneurol.2013.22
  3. 3. Situation SPINAL CORD INJURY Every year, between 250 000 and 500 000 people become spinal cord injured. (WHO 2013) “pi al ord i jur is a medically complex and life-disrupting condition, notes Dr. Etienne Krug, Director of the Department of Violence and Injury Prevention and Disability, WHO. However, spinal cord injury is preventable, survivable, and need not preclude good health and social inclusion.
  4. 4. Situation STROKE Is the leading cause of serious long-term disability. (Mozaffarian et al. 2015) While I speak 5 persons in US will die consequence of stroke. (Mozaffarian et al. 2015) Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015 ;e29-322. STROKE SCI TBI
  5. 5. Current treatment approach Preventable diseases Shin, S.S., Dixon, C.E., Okonkwo, D.O., Richardson, R.M., 2014. Neurostimulation for traumatic brain injury. J. Neurosurg. 121, 1219–1231. doi:10.3171/2014.7.JNS131826 Fehlings, M.G., Vawda, R., 2011. Cellular Treatments for Spinal Cord Injury: The Time is Right for Clinical Trials. Neurotherapeutics 8, 704– 720. doi:10.1007/s13311-011-0076-7 Burns, T.C., Verfaillie, C.M., Low, W.C., 2009. Stem Cells for Ischemic Brain Injury: A Critical Review. J. Comp. Neurol. 515, 125–144. doi:10.1002/cne.22038 TBI: Durable treatments for neurological function deficits following TBI have been elusive, as there are currently no FDA-approved therapeutic modalities for mitigating the consequences of TBI. (Shin et al. 2014) SCI: Despite advances in pre-hospital care, medical and surgical management, and rehabilitation approaches, many SCI sufferers still experience substantial neurological disability. (Fehlings et al. 2011) STROKE: Unfortunately, although a plethora of neuroprotective compounds have shown promise in animal models, no other treatment to date has shown efficacy in clinical trials (Burns et al. 2009)
  6. 6. Rationale of aBM-SC A scanning electron microscope picture of a nerve ending. It has been broken open to reveal vesicles (orange and blue) containing chemicals used to pass messages in the nervous system. TINA CARVALHO Secrete all kind of factors, which influence the direct environment of injured cells: (Gnecchi et al. 2008, Caplan et al. 2006). ASC in BM (HSCs and MSCs) Induce NEUROPROTECTION, inflammatory suppression and neural repair, allowing reconstruction of totally damaged tissues or preventing partially damaged cells from evolving to cell demise. (Erceg and Stojkovic, 2009) Gnecchi, M., Zhang, Z., Ni, A., Dzau, V.J., 2008. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res. 103, 1204–1219. doi:10.1161/CIRCRESAHA.108.176826 Caplan, A.I., Dennis, J.E., 2006. Mesenchymal stem cells as trophic mediators. J. Cell. Biochem. 98, 1076–1084. doi:10.1002/jcb.20886 Erceg, S.M.R. and M. Stojkovic, 2009. Human embryonic stem cell differentiation toward regional specific neural precursors. Stem Cells, 1: 78-87. DOI: 10.1634/stemcells.2008-0543
  7. 7. Rationale of aBM-SC Zhang H, Zhang N, Li M, Feng H, Jin W, Zhao H, Chen X, Tian L (2008) Therapeutic angiogenesis of bone marrow mononuclear cells (MNCs) and peripheral blood MNCs: transplantation for ischemic hindlimb. Ann Vasc Surg 22:238–247 Zeng, R., Wang, L.-W., Hu, Z.-B., Guo, W.-T., Wei, J.-S., Lin, H., Sun, X., Chen, L.-X., Yang, L.-J., 2011. Differentiation of human bone marrow mesenchymal stem cells into neuron-like cells in vitro. Spine 36, 997–1005. doi:10.1097/BRS.0b013e3181eab76 Bareyre, F.M., 2008. Neuronal repair and replacement in spinal cord injury. J. Neurol. Sci. 265, 63–72. doi:10.1016/j.jns.2007.05.004 Kucia, M., Reca, R., Jala, V.R., Dawn, B., Ratajczak, J., Ratajczak, M.Z., 2005. Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia 19, 1118–1127. doi:10.1038/sj.leu.2403796 aBM-SC are easy to harvest from the iliac crest and a gradient centrifugation can separate the buffy coat layer, which contains the highest concentration of HSCs and MSCs. ASC in BM (HSCs and MSCs) • Stimulate neovascularization and increase oxygenation (Zhang et al. 2008). • Transdifferentiate into specific neuronal cells (Zeng et al. 2011). • Promote synaptic connections (Bareyre et al. 2008). • Promote neuroplasticity (Kucia et al. 2005). NO Ethic or immune rejection concrens
  8. 8. Brain Injury Cox CS, Baumgartner JE Jr, Harting MT et al (2011) Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery 68:588– 600 Tian, C., Wang, X., Wang, X., Wang, L., Wang, X., Wu, S., Wan, Z., 2013. Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture. Exp. Clin. Transplant. Off. J. Middle East Soc. Organ Transplant. 11, 176–181. doi:10.6002/ect.2012.0053 (Cox et al. 2005) BMN MSC- Open label study in adults with sub acute Subacute sever TBI (N=97) 38 of 97 patients (39.2%) HSC autolog (1 month) TBI; follow up 15 days. 1 × 106 cells/mL (5 ml.) with TBI improved. Eleven of 24 patients (45.8%) with persistent vegetative state showed post therapeutic improvements in consciousness (P = .024) (Tian et al. 2013)
  9. 9. Spinal Cord Injury Park DH, Eve DJ, Chung YG, Sanberg PR (2010) Regenerative medicine for neurological disorders. ScientificWorldJ 10:470–489 Sykova E, Homola A, Mazanec R et al (2006) Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 15:675–687 (Park et al. 2005) (Sykova et al. 2006)
  10. 10. Spinal Cord Injury Yoon SH, Shim YS, Park YH et al (2007) Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: phase I/II clinical trial. Stem Cells 25:2066–2073. Geffner LF, Santacruz P, Izurieta M et al (2008) Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant 17:1277–1293 (Yoon et al. 2007) (Geffner et al. 2008) ACUTE VS. CHRONIC ADMINISTRATION
  11. 11. Stroke Denes, A., Coutts, G., Lénárt, N., Cruickshank, S.M., Pelegrin, P., Skinner, J., Rothwell, N., Allan, S.M., Brough, D., 2015. AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc. Natl. Acad. Sci. 201419090. doi:10.1073/pnas.1419090112. Friedrich MA, Martins MP, Araujo MD et al (2012) Intra-arterial infusion of autologous bone-marrow mononuclear cells in patients with moderate to severe middle- cerebral-artery acute ischemic stroke. Cell Transplant 21(Suppl 1):13–21 Savitz SI, Misra V, Kasam M et al (2011) Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol 70:59–69 These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain. (Denes et al. 2015) (Friedrich et al. 2008) (Savitz et al. 2008)
  12. 12. ACUTE TREATMENT PROTOCOL The earl the etter ut if dela ed ot o trai di ated.
  13. 13. POint-of-Care Stem cell Therapy (POCST) 200 cc of BM Aktas, M., Radke, T.F., Strauer, B.E., Wernet, P., Kogler, G., 2008. Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax. Cytotherapy 10, 203–211. doi:10.1080/14653240701851324. Cox CS, Baumgartner JE Jr, Harting MT et al (2011) Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery 68:588–600 Autologous bone marrow-derived stem cells transplant with on-site cell concentration for non-hematopoietic diseases. The o e arrow olle tio i the a ute phase of the brain injury did not cause hemodynamic disturbances and was well tolerated Co et al. TBI i hildre i the first 8 hours) Minimal cell manipulation and effective separation (Aktas et. al. 2008)
  14. 14. After 25 minutes • IT: 8.5 million CD34+ cells in 12 millilitres. • IV: 5.6 million CD34+ cells in 8 millilitres. Matzner, Shaw C., Morrice J., Ruiz-Navarro F., Kobinia G., 2014. CD34+ cell counts and their relationship to clinical factors in 281 patients undergoing Autologous Stem Cell Transplant, in: World Stem Cell Regenerative Medicine Congress. Farivar, S., Mohamadzade, Z., Shiari, R., Fahimzad, A., 2015. Neural differentiation of human umbilical cord mesenchymal stem cells by cerebrospinal fluid. Iran. J. Child Neurol. 9, 87–93. CSF induces differentiation of SC into neurons (Matzner et al. 2014) (Farivar et al. 2015) CD34+ according to the ISHAGE guidelines. Viability was assessed with 7-Aminoactinomycin D (7-AAD) dye.
  15. 15. Lumbar Puncture? Bakshi, A., Hunter, C., Swanger, S., Lepore, A., Fischer, I., 2004. Minimally invasive delivery of stem cells for spinal cord injury: advantages of the lumbar puncture technique. J. Neurosurg. Spine 1, 330–337. doi:10.3171/spi.2004.1.3.0330 Bakshi, A., Barshinger, A.L., Swanger, S.A., Madhavani, V., Shumsky, J.S., Neuhuber, B., Fischer, I., 2006. Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation. J. Neurotrauma 23, 55–65. doi:10.1089/neu.2006.23.55 The use of LP and interventricular routes allows more efficient delivery of cells to the injured cord compared with the intravenous route. (Bakshi et al. 2004) We found that MSC delivered by LP reached the contused spinal cord tissues and exerted a significant beneficial effect by reducing cyst and injury size. (Bakshi et al. 2006)
  16. 16. Our results in chronic patients 61 patients SCI follow-up after 6 months Mean time since diagnosis was 72 months NO PATIENT PRESENT MAYOR SIDE EFFECTS 62% improved the muscular strength 50% improved the spasticity 37% improved the bladder control 93% of them referred a better general health status 50% had an improved sensibility
  17. 17. Conclusions Clinical safety Reproducibility Effectiveness
  18. 18. Future • Imaging Stem cell trackers in humans. • Protocol of treatment in the first 5 days after presentation. READY FOR A Randomized controlled Trial in acute patients
  19. 19. Dr. med. Francisco Ruiz-Navarro PI: Pof. Dr. Med. GEORG KOBINIA