(优选)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、（优选）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 Lindvall 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 gra

2、fted neuronsSynuclein-HostUbiquintin-HostSynuclein-Grafted NeuronsUbiquintin-Grafted NeuronsGrafted nigral neurons were 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.Transplanted dopamine

3、neurons in people with PD do not contain Lewy bodiesMendez, Isacson et al, , NATURE MEDICINE VOLUME 14 (5):507-509, 2008Freed 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 transplantation and 15 of these subjects who

4、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 480 | NATURE | 547，Lorenz Studer，et al Me

5、morial Sloan-Kettering Cancer CenterImproved Cell Therapy Protocol for Parkinsons Disease Based on Differentiation Efficiency and Safety of hESC-, Hipsc and Non-Human Primate iPSC-Derived DA NeuronsIsacson et al, , Stem Cells. 2013 ;31(8):1548-62.Dopamine release from transplanted neural stem cells

6、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 Non-Human Primate Model of Parkinsons Disease Cell Stem Cell. 2015 Mar 5;16(3):269-74. Ole Isacson et al，Harvard Stem Cell Institu

7、teStem 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 2013, involved the transplan-tation of human spinal cord-derived NSCs into the spinal cord of 15 late to mid-stage ALS patients Gl

8、ass, Feldman, E.L., 2012. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 30 (6), 1144 1151. Riley, J., Feldman, E.L., 2014. “Intraspinal stem cell transplantation in ALS: a phase I trial, cervica

9、l microinjection and final surgical safety outcomes”. Neurosurgery 74 (1), 77 87RESULTS: Unilateral cervical (group D, n = 3) and cervical plus thoracolumbar (group E, n = 3) microinjections to the ventral horn have been completed in ambulatory patients. One patient developed a postoperative kyphoti

10、c 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: Delivery of a cellular payload to the cervical or

11、 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. Intraspinal stem cell transplantation in ALS: a phase I t

12、rial, 2014iPS Cells Were Generated from PD patients and Normal Controls 6-OHDA-induced Rat PD ModelHuman 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 横断损伤产生后肢瘫痪。 C. 无脊髓损伤的

13、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移植神经干细胞分化的神经轴索与宿主脊髓神经细胞及其树突形成突触连接 Lu P et al，Cell. 2012 Septemb

14、er 14; 150(6): 12641273Bone Marrow Stromal Cell Intraspinal Transplants 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, compressivesp

15、inal cord injury(SCI) in Sprague Dawley rats.Cellswere administered 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 neuroprotecti

16、on. two months post-injuryin a clinically relevant model of severe 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 ofi

17、njurywithin days are unlikely to be beneficial. Intraspinal Stem 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 ; De

18、partment of Neurology, Emory University, Atlanta, Georgia; Department of Neurology, University of Michigan, Ann Arbor, Michigan神经干细胞移植方法 Each microinjection series comprised 5 injections (10mL/injection) separated by 4 mm. Each injection :100 000 neural stem cells derived from a fetal spinal cord. T

19、welve patients were treated with either unilateral or bilateral injections. Patients are followed clinically and radiologically to assess potential toxicity of the procedure.Lumbar LaminectomyMicroinjection platform applicationPostoperative imaging progressionRiley, J., Feldman, E.L., 2014. “Intrasp

20、inal stem cell transplantation in ALS: a phase I trial, cervical microinjection and final surgical safety outcomes”. 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 Molecu

21、lar Mechanism of Stem Cell Transplantation for Neurological DiseasesTransplanted cells survive，differentiate to neurons, astrocytes,oligodendrocyte precursors (hESC, hiPSC, NSC ) and release neurological transmittors such as dopamine,Ach. Release of neurotrophic factors (GDNF, GDNE,IGF,) to increase

22、 the functions of the endogenous neural stem cellsRelease of immuno-regulatory factors such as IL-2, 6,8,10 to 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， 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 ex