神经退行性疾病干细胞移植治疗：目前研究现状与未来展望课件

1、韩发彬，MD，PhD泰山医学院聊城临床学院干细胞与再生医学实验室2015，10，31神经退行性疾病干细胞移植治疗：目前研究现状与未来展望Stem Cell Sources for Treatment of Neurological Diseases (AD, PD, ALS, MS, Stroke, SCI)Fabin Han, et al, Journal of Neurorestoratology 2015:3 112胎儿神经干细胞治疗帕金森氏病临床研究发展历程Evans JR, Mason SL, Barker RA. Prog Brain Res. 2012;200:169-98 Li

2、ndvall O, et al，Nat Med. 2008 May;14(5):501-3THSynucleinOverlayTransplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neuronsSynuclein-HostUbiquintin-HostSynuclein-Grafted NeuronsUbiquintin-Grafted NeuronsGrafted nigral neurons w

3、ere found to have Lewy body-like inclusions14 years after transplantation into the striatum of an individual with PDOlanow CW. et al Nat Med. 2008May;14(5):504-6.Freed CR, J Nucl Med. 2010 Jan;51(1):7-15 - Long term Study- 33 of the original trial participants who were followed for 2 years after tra

4、nsplantation and 15 of these subjects who were followed for 2 additional years. - These results suggest that clinical benefit and graft viability are sustained up to 4 y after transplantation. Freed CR, Neurotherapeutics (2011) 8:549 561人体胚胎干细胞分化的多巴胺神经元移植改善小鼠，大鼠和猴子帕金森氏病的运动障碍22/29 DECEMBER 2011 | VOL

5、 480 | NATURE | 547，Lorenz Studer，et al Memorial Sloan-Kettering Cancer CenterDopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo. Zhou z, et al, Proc Natl Acad Sci U S A.2014 Nov 4;111(44):15804-9iPSC-Derived Dopamine Neurons function after Transplantation in a

6、 Non-Human Primate Model of Parkinsons Disease Cell Stem Cell. 2015 Mar 5;16(3):269-74. Ole Isacson et al，Harvard Stem Cell InstituteStem cell-based Clinical Trials for (ALS) Nuralstem, In c . the first Phase I clinical trial for a stem cell-based treatment of ALS. Initiated in 2010 and completed in

7、 2013, involved the transplan-tation of human spinal cord-derived NSCs into the spinal cord of 15 late to mid-stage ALS patients RESULTS: Unilateral cervical (group D, n = 3) and cervical plus thoracolumbar (group E, n = 3) microinjections to the ventral horn have been completed in ambulatory patien

8、ts. One patient developed a postoperative kyphotic deformity prompting completion of a laminoplasty in subsequent patients. Another required reoperation for wound dehiscence and infection. The solitary patient with bulbar amyotrophic lateral sclerosis required perioperative reintubation.CONCLUSION:

9、Delivery of a cellular payload to the cervical or thoracolumbar spinal cord was well tolerated by the spinal cord in this vulnerable population. This encouraging finding supports consideration of this delivery approach for neurodegenerative, oncologic, and traumatic spinal cord afflictions. Intraspi

10、nal stem cell transplantation in ALS: a phase I trial, 2014iPS Cells Were Generated from PD patients and Normal Controls Human iPS cells Integrated to the Host Brain of 6-OHDA-induced Rat PD ModelHan F, Wang W, Chen C, Duan J, et al Cytotherapy 2015 分化的胎脑神经干细胞移植治疗PD建立大鼠SCI损伤模型A. 暴露和部分横切脊髓外科手术。 B. T7

11、 横断损伤产生后肢瘫痪。 C. 无脊髓损伤的正常大鼠。RT-PCR to Detect the MicroRNA Expression in Rat SCI Model MiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181aReal-Time RT-PCR to Detect the MicroRNA Expression in SCI干细胞移植修复脊髓神经损伤Bone Marrow Stromal Cell Intraspinal Tran

12、splants Fail to Improve Motor Outcomes in a Severe Model ofSCIJournal of Neurotrauma 2015， Tuszynski MHTo determine whether local mechanisms mediate BMSC neuroprotective actions grafted allogeneic BMSCs to sites of severe, compressivespinal cord injury(SCI) in Sprague Dawley rats.Cellswere administe

13、red 48 hours after the originalinjury. Additional animals received allogeneic MSCs that were genetically modified to secrete BDNF, to further determine whether a locally administered neurotrophic factor provides or extends neuroprotection. two months post-injuryin a clinically relevant model of seve

14、re SCI, BMSC grafts with or without BDNF secretion failed to improve motor outcomes. Thus, allogeneic grafts of BMSCs do not appear to act through local mechanisms, and futureclinical trialsthat acutely deliver BMSCs to actual sites ofinjurywithin days are unlikely to be beneficial. Intraspinal Stem

15、 Cell Transplantation in Amyotrophic Lateral Sclerosis: A Phase I SafetyTrial, Technical Note, and Lumbar Safety OutcomesNEUROSURGERY VOLUME 71 | NUMBER 2 | AUGUST 2012Department of Neurosurgery, EmoryUniversity , Atlanta , Georgia ; Department of Neurology, Emory University, Atlanta, Georgia; Depar

16、tment of Neurology, University of Michigan, Ann Arbor, MichiganLumbar LaminectomyMicroinjection platform applicationPostoperative imaging progressionRiley, J., Feldman, E.L., 2014. “Intraspinal stem cell transplantation in ALS: a phase I trial, cervical microinjection and final surgical safety outco

17、mes”. Neurosurgery 74 (1), 77 87 Clinical Trials using ESCs and iPSCsThere is also a report of one Japanese patient who received a transplant of asheet of iPSC-derived RPE Summary on Molecular Mechanism of Stem Cell Transplantation for Neurological DiseasesTransplanted cells survive，differentiate to

18、 neurons, astrocytes,oligodendrocyte precursors (hESC, hiPSC, NSC ) and release neurological transmittors such as dopamine,Ach. Release of neurotrophic factors (GDNF, GDNE,IGF,) to increase the functions of the endogenous neural stem cellsRelease of immuno-regulatory factors such as IL-2, 6,8,10 to

19、play immuno-modulation and attenuation of the inflammatory process, such as MSC.The transplanted cells formed synapse with host cells.Others such as delaying the onset and prolonging survival of SOD1 rats Increasing host neurogenesis 今后干细胞治疗神经退行性疾病的临床研究需要考虑的问题1. Cell Sources： Neural projenitors， MSC

20、， hES cells， iPS cells 2. SC grafting should be conducted to ensure 100,000 dopaminergic neurons （PD）survive per transplantation site.3. SC grafts should exhibit regulated release of dopamine in line with that of endogenous dopaminergic neurons.4. By reestablishing the striatal dopaminergic system, grafts should show the capacity to restore functional connectivity within the basal ganglia and at