神經(jīng)退行性疾病干細胞移植治療目前研究現(xiàn)狀與未來展望

1、韓發(fā)彬，MD，PhD泰山醫(yī)學(xué)院聊城臨床學(xué)院干細胞與再生醫(yī)學(xué)實驗室2015，10，31,神經(jīng)退行性疾病干細胞移植治療：目前研究現(xiàn)狀與未來展望,Stem Cell Sources for Treatment of Neurological Diseases (AD, PD, ALS, MS, Stroke, SCI),Fabin Han, et al, Journal of Neurorestoratology 2015:3 1–

2、12,胎兒神經(jīng)干細胞治療帕金森氏病臨床研究發(fā)展歷程,Evans JR, Mason SL, Barker RA. Prog Brain Res. 2012;200:169-98,Lindvall O, et al，Nat Med. 2008 May;14(5):501-3,TH,Synuclein,Overlay,Transplanted fetal mesencephalic dopaminergic neurons (11-16 y

3、ears) developed alpha-synuclein-positive Lewy bodies in grafted neurons,Synuclein-Host,Ubiquintin-Host,Synuclein-Grafted Neurons,Ubiquintin-Grafted Neurons,Grafted nigral neurons were found to have Lewy body-like inclusi

4、ons14 years after transplantation into the striatum of an individual with PD,Olanow CW. et al Nat Med. 2008May;14(5):504-6.,Transplanted dopamine neurons in people with PD do not contain Lewy bodies,Mendez, Isacson et

5、 al, , NATURE MEDICINE VOLUME 14 (5):507-509, 2008,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 transplantation and 15 of these

6、 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,人體胚胎干細胞分

7、化的多巴胺神經(jīng)元移植改善小鼠，大鼠和猴子帕金森氏病的運動障礙,22/29 DECEMBER 2011 | VOL 480 | NATURE | 547，Lorenz Studer，et al Memorial Sloan-Kettering Cancer Center,Improved Cell Therapy Protocol for Parkinson’s Disease Based on Differentiation Eff

8、iciency and Safety of hESC-, Hipsc and Non-Human Primate iPSC-Derived DA Neurons,Isacson et al, , Stem Cells. 2013 ;31(8):1548-62.,Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo

9、.,Zhou z, et al, Proc Natl Acad Sci U S A.2014 Nov 4;111(44):15804-9,iPSC-Derived Dopamine Neurons function after Transplantation in a Non-Human Primate Model of Parkinson’s Disease,Cell Stem Cell. 2015 Mar 5;16(3):269-7

10、4. Ole Isacson et al，Harvard Stem Cell Institute,Stem 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

11、 2013, involved the transplan-tation of human spinal cord-derived NSCs into the spinal cord of 15 late to mid-stage ALS patients,Glass, Feldman, E.L., 2012. Lumbar intraspinal injection of neural stem cells in patients w

12、ith 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, cervical micr

13、oinjection and final surgical safety outcomes”. Neurosurgery 74 (1), 77 –87,RESULTS: Unilateral cervical (group D, n = 3) and cervical plus thoracolumbar (group E, n = 3) microinjections to the ventral horn have been com

14、pleted in ambulatory patients. One patient developed a postoperative kyphotic deformity prompting completion of a laminoplasty in subsequent patients. Another required reoperation for wound dehiscence and infection. The

15、solitary patient with bulbar amyotrophic lateral sclerosis required perioperative reintubation.CONCLUSION: Delivery of a cellular payload to the cervical or thoracolumbar spinal cord was well tolerated by the spinal cor

16、d 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

17、 ALS: a phase I trial, 2014,iPS Cells Were Generated from PD patients and Normal Controls,6-OHDA-induced Rat PD Model,Human iPS cells Integrated to the Host Brain of 6-OHDA-induced Rat PD Model,Han F, Wang W, Chen C, Dua

18、n J, et al Cytotherapy 2015,分化的胎腦神經(jīng)干細胞移植治療PD,建立大鼠SCI損傷模型,A. 暴露和部分橫切脊髓外科手術(shù)。 B. T7 橫斷損傷產(chǎn)生后肢癱瘓。 C. 無脊髓損傷的正常大鼠。,RT-PCR to Detect the MicroRNA Expression in Rat SCI Model,Real-Time RT-PCR to Detect the MicroRNA Expression i

19、n SCI,,干細胞移植修復(fù)脊髓神經(jīng)損傷,移植神經(jīng)干細胞分化的神經(jīng)軸索與宿主脊髓神經(jīng)細胞及其樹突形成突觸連接,Lu P et al，Cell. 2012 September 14; 150(6): 1264–1273,Bone Marrow Stromal Cell Intraspinal Transplants Fail to Improve Motor Outcomes in a Severe Model of SCI,J

20、ournal of Neurotrauma 2015， Tuszynski MHTo determine whether local mechanisms mediate BMSC neuroprotective actions grafted allogeneic BMSCs to sites of severe, compressive spinal cord injury (SCI) in Sprague

21、Dawley rats. Cells were administered 48 hours after the original injury. Additional animals received allogeneic MSCs that were genetically modified to secrete BDNF, to further determine whether a locally

22、administered neurotrophic factor provides or extends neuroprotection. two months post-injury in a clinically relevant model of severe SCI, BMSC grafts with or without BDNF secretion failed to improve motor outcomes

23、. Thus, allogeneic grafts of BMSCs do not appear to act through local mechanisms, and future clinical trials that acutely deliver BMSCs to actual sites of injury within days are unlikely to be benefic

24、ial.,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 Neurosurger

25、y, EmoryUniversity , Atlanta , Georgia ; Department of Neurology, Emory University, Atlanta, Georgia; Department of Neurology, University of Michigan, Ann Arbor, Michigan,神經(jīng)干細胞移植方法,Each microinjection series comprised 5

26、 injections (10mL/injection) separated by 4 mm. Each injection :100 000 neural stem cells derived from a fetal spinal cord. Twelve patients were treated with either unilateral or bilateral injections. Patients ar

27、e followed clinically and radiologically to assess potential toxicity of the procedure.,Lumbar Laminectomy,Microinjection platform application,Postoperative imaging progression,Riley, J., Feldman, E.L., 2014. “Intraspina

28、l 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 iPSCs,There is also a report of one Japanese

29、patient who received a transplant of asheet of iPSC-derived RPE,Summary on Molecular Mechanism of Stem Cell Transplantation for Neurological Diseases,Transplanted cells survive，differentiate to neurons, astrocytes,oligo

30、dendrocyte 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 cellsRel

31、ease 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 th

32、e onset and prolonging survival of SOD1 rats Increasing host neurogenesis,今后干細胞治療神經(jīng)退行性疾病的臨床研究需要考慮的問題,1. Cell Sources： Neural projenitors， MSC， hES cells， iPS cells 2. SC grafting should be conducted to ensure > 100

33、,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 dopaminerg

34、ic system, grafts should show the capacity to restore functional connectivity within the basal ganglia and at extra-striatal loci.5. Long-lasting and significant symptom- relief must be achieved （over 2-3 years）.6. Ev

35、aluation System （Symptoms, Dopamine release, Levodopa-response), Unified Parkinson ’s Disea se Ra ting Scal e (UPDRS)，Biomarkers7. Adverse effects must be minimal. This include s the absence of tumor formation and GIDs

36、（graf t-induced dyskinesia） throughout long-term follow-up periods.8. Sample Size： over 50-100 patients。,致謝/Acknowledgements,北京大學(xué)生命科學(xué)研究中心康新江博士干細胞與再生醫(yī)學(xué)實驗室全體科研人員： 王偉，張男，陳超，李森，盧現(xiàn)杰，段婧，吳士超，宋昊，宋娜，陳清法，劉延明,干細胞與再生醫(yī)學(xué)實驗室研