regenerative medicine in the brain and the spinal cord spinal cord injuries
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1 regenerative medicine in the brain and the spinal cord spinal cord injuries
2 primary and secondary events during SCI traumatic spinal cord injury (SCI)
3 traumatic spinal cord injury (SCI) main goal is to prevent neuronal necrosis, excitatory injuries and oligodendroglia apoptosis and later to promote axonal regeneration
4 primary and secondary events during SCI (spinal cord injury) traumatic spinal cord injury (SCI)
5 traumatic spinal cord injury (SCI) major events during acute / subacute / chronic injury hemorrhage, edema, proapoptotic factors, demyelination, inflammation astrogliosis, demyelination, inflammation, microcavities cystic cavity, astroglial scar tissue, fibrous deposit of CSPG
6 traumatic spinal cord injury (SCI) injured CNS axon can grow into a PNS axon-explant -> external inhibition is the predominant cause main factors hindering successful regeneration: inhibiting neurite outgrowth - glial scar tissue strong CSPG (chondroitin sulfphate proteoglycan) secretion [aggrecan, brevican, syndecan, versican, NG2...] - myelin debris - MAG (myelin-associated glicoprotein), - Omgp (oligodendrocytemyelin glicoprotein), - Nogo-A / reticulon 4A,
7 traumatic spinal cord injury (SCI) glial scar: possessing both protective and inhibitory functions! successful therapy depends greatly on the onset and extent of antiglial scar treatment
8 traumatic spinal cord injury (SCI) glial scar: needed for axon regeneration? Nature Apr 14;532(7598):
9 traumatic spinal cord injury (SCI) optimal time for transplantation is limited and depends on the timescale of SCI phase
10 animal models for spinal cord injury (SCI) transection lesion: reproducible, but with limited clinical relevance (does not mimic the most frequent crush injuries; meninges are disrupted) contusion model: direct damage resulting from membrane disruption, vascular damage and hemorrhage crush model: the most appropriate but its severness is limited by the survival chances of the animals (intensive care is not possible; omly mild/moderate injuries) differences between rodent and human spinal cord circuitry: rodent locomotor system is far less dependent on corticospinal input than primate and human systems; in humans, direct connections between cortical and spinal motor neurons are well developed high rates of spontaneous recovery in moderate and incomplete injuries - complicate assessment of efficacy parameters to assess treatment efficacy? clinical assessment scales, imaging, neurophysiological outcomes...
11 animal models for spinal cord injury (SCI) /Stem-Cell-Implants-Improve-Monkeys--Grip- After-Spinal-Cord-Injury/ hnscs can be successfully engrafted to fill the large lesion cavity of a nonhuman primate spinal cord special protocol: more fibrinogen thrombin in the grafting mixture; intraoperative drainage of CSF prolonged time period of maturation regeneration of corticospinal axons; many human axons extend into the host grey matter
12 potential stem cell therapies in SCI cell replacement - oligodendrocytes to facilitate myelination of spared axons - replenish neurons to repair intraspinal circuitry and improve functional recovery - no neurogenic niche in the spinal cord? <-> ependymal lining (astrocyte differentiation?) - ES / ips / NPC / fetal CNS / non-neuronal stem cells (bone marrow, umbilical cord, etc) - often in combination with growth factors (eg, BDNF)
13 potential stem cell therapies in SCI neuroprotection and trophic support - promote survival of host cells at the lesion site - prevent atrophy and loss of corticospinal projection neurons with damaged / demyelinated axons - can alter the responses of endogenous progenitor cells / surviving local neurons
14 potential stem cell therapies in SCI facilitating axon regeneration - transplanting Schwann cell grafts or olfactory ensheathing cells to create a permissive environment for axon regeneration - fill lesion cavities with grafted cells to act as permissive substrates for axon outgrowth - often in combination with growth factors or with counteracting inhibitory factors (chondroitinase-abc to degrade CSPG; anti-nogo A)
15 potential stem cell therapies in SCI
16 potential stem cell therapies in SCI cell transplantation + biomaterials
17 potential stem cell therapies in SCI reprogramming - in situ; viral application
18 ethical considerations for SCI stem cell therapies reliable animal model of injury? time of transplantation /level and severity of injury: important factors in determining appropriate participants for clinical trials cervical injuries are more common than thoracic or lumbar injuries, but errors in treatment of cervical injuries can be far more devastating how to measure the effectiveness of the transplantation? spontaneous recovery? risk of tumor formation /neuropathic pain how to track implanted cells? unreliable results based on studies/news from - emerging nations - open label studies - uncontrolled studies
19 Clinical trials to cure SCI 2010 s: little evidence of clinically significant benefits
20 Clinical trials to cure SCI Stem Cell Inc: single-blind, randomized, parallel arm, phase II Proof-of-Concept study for the safety and efficacy of HuCNS-SC transplantation in cervical SCI
21 Clinical trials to cure SCI Stem Cell Inc: single-blind, randomized, parallel arm, phase II Proof-of-Concept study for the safety and efficacy of HuCNS-SC transplantation in cervical SCI - HuCNS-Sc, transplantation within 3-12 months after injury - interim 6-month data showed improvements in motor strength in 4/5 subjects, - observations up to one year could not find a trend for the improvement over time, - study terminated in 2016
22 Clinical trials to cure SCI olfactory mucosal biopsy, culture of olfactory ensheathing cells, intraspinal cell grafting; some improvements, no negative effects
23 Clinical trials to cure SCI Asterias Biotherapeutics Inc: open-label, single-arm, phase I/IIa study for severe cervical SCI, using human ESC-derived oligodendrocyte progenitor cells (OPCs)
24 Clinical trials to cure SCI Asterias Biotherapeutics Inc: open-label, single-arm, phase I/IIa study for severe cervical SCI, using human ESC-derived oligodendrocyte progenitor cells (OPCs) (15/18) and 100% (6/6) of the patients showed motor recovery at six and 12 months, respectively - no serious, unexpected, adverse events related to AST-OPC1, the surgical procedure, or the drug used for immunosuppression in any of the total of 30 patients O4&feature=youtu.be
25 Ethical problems
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