药学学报, 2019, 54(5): 788-800
引用本文:
彭雨晨, 冯新红, 张泳, 黄龙舰, 赵春阳, 王晓良, 王庆利, 彭英. 肌萎缩性侧索硬化症非临床药效学评价体系的探索[J]. 药学学报, 2019, 54(5): 788-800.
PENG Yu-chen, FENG Xin-hong, ZHANG Yong, HUANG Long-jian, ZHAO Chun-yang, WANG Xiao-liang, WANG Qing-li, PENG Ying. Exploration of non-clinical pharmacodynamics evaluation system of amyotrophic lateral sclerosis[J]. Acta Pharmaceutica Sinica, 2019, 54(5): 788-800.

肌萎缩性侧索硬化症非临床药效学评价体系的探索
彭雨晨1, 冯新红2, 张泳1, 黄龙舰1, 赵春阳3, 王晓良1, 王庆利3, 彭英1
1. 中国医学科学院、北京协和医学院药物研究所, 北京 100050;
2. 清华大学附属北京清华长庚医院神经内科, 北京 102218;
3. 国家药品监督管理局药品审评中心, 北京 100038
摘要:
肌萎缩性侧索硬化(amyotrophic lateral sclerosis,ALS)是运动神经元病的最常见类型,其发病机制尚不明确。近年来,对于ALS遗传基础的研究进展促进了各种ALS疾病模型的出现和发展,为ALS相关药物及治疗方法的筛选提供了多种选择。本综述主要介绍肌萎缩性侧索硬化症的相关研究进展,对典型的非临床动物模型药物筛选评价体系进行归纳,包括转基因动物模型、基因敲除动物模型及自然发病动物模型,总结了规范化ALS非临床研究需要注意的问题,并对系统性规范化的非临床药效学研究方案提出建议。
关键词:    肌萎缩性侧索硬化症      非临床药效学研究      超氧化物歧化酶1      动物模型     
Exploration of non-clinical pharmacodynamics evaluation system of amyotrophic lateral sclerosis
PENG Yu-chen1, FENG Xin-hong2, ZHANG Yong1, HUANG Long-jian1, ZHAO Chun-yang3, WANG Xiao-liang1, WANG Qing-li3, PENG Ying1
1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2. Department of Neurology, Beijing Tsinghua Changgung Hospital, Beijing 102218, China;
3. Center for Drug Evaluation, National Medical Product Administration, Beijing 100038, China
Abstract:
Amyotrophic lateral sclerosis (ALS) is among the most common type of motor neuron diseases, and its pathogenesis remains unclear. In recent years, our understanding of the genetic basis of ALS has led to the development of various ALS disease models, which allow for screening of ALS-related drugs and treatment methods. This review focuses on the research progress of ALS, summarizes the systems of commonly used experi mental animal models, including transgenic animals, gene knockout approaches and autonomous animal models, points to the problems needing attention in standardized ALS non-clinical research, and proposes the criteria for selection of standardized R&D model.
Key words:    amyotrophic lateral sclerosis    non-clinical pharmacodynamics    superoxide dismutase 1    animal model   
收稿日期: 2018-12-24
DOI: 10.16438/j.0513-4870.2018-1141
基金项目: 国家"重大新药创制"科技重大专项(2018ZX09711001-003-005,2018ZX09711001-003-009);中国医学科学院医学与健康科技创新工程(2017-I2M-2-004);新药作用机制研究与药效评价北京市重点实验室(BZ0150);北京市医院管理局青苗计划专项经费资助(QML20170902).
通讯作者: 王庆利,Tel:86-10-63165173,Fax:86-10-63017757,E-mail:ypeng@imm.ac.cn;彭英,Tel:86-10-85243836,Fax:86-10-68584189,E-mail:wangql@cde.org.cn
Email: ypeng@imm.ac.cn;wangql@cde.org.cn
相关功能
PDF(466KB) Free
打印本文
0
作者相关文章
彭雨晨  在本刊中的所有文章
冯新红  在本刊中的所有文章
张泳  在本刊中的所有文章
黄龙舰  在本刊中的所有文章
赵春阳  在本刊中的所有文章
王晓良  在本刊中的所有文章
王庆利  在本刊中的所有文章
彭英  在本刊中的所有文章

参考文献:
[1] Mitchell JC, Constable R, So E, et al. Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS[J]. Acta Neuropathol Commun, 2015, 3:36.
[2] Fidler JA, Treleaven CM, Frakes A, et al. Disease progression in a mouse model of amyotrophic lateral sclerosis:the influence of chronic stress and corticosterone[J]. FASEB J, 2011, 25:4369-4377.
[3] Zhang Z, Wang SS, Zhu TB, et al. Rg1 alleviates the damage in ALS model through regulation of miR153/Nrf2/HO-1[J]. Acta Pharm Sin (药学学报), 2018, 53:546-552.
[4] Ferraiuolo L, Kirby J, Grierson AJ, et al. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis[J]. Nat Rev Neurol, 2011, 7:616-630.
[5] Picher-Martel V, Valdmanis PN, Gould PV, et al. From animal models to human disease:a genetic approach for personalized medicine in ALS[J]. Acta Neuropathol Commun, 2016, 4:70.
[6] Johann S, Heitzer M, Kanagaratnam M, et al. NLRP3 inflamma some is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients[J]. Glia, 2015, 63:2260-2273.
[7] Mathis S, Couratier P, Julian A, et al. Management and thera peutic perspectives in amyotrophic lateral sclerosis[J]. Expert Rev Neurother, 2017, 17:263-276.
[8] Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyo trophic lateral sclerosis[J]. Nature, 1993, 362:59-62.
[9] Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)[J]. Cochrane Database Syst Rev, 2012, 3:14.
[10] Yoshida H, Yanai H, Namiki Y, et al. Neuroprotective effects of edaravone:a novel free radical scavenger in cerebrovascular injury[J]. CNS Drug Rev, 2006, 12:9-20.
[11] Martinez A, Palomo Ruiz MD, Perez DI, et al. Drugs in clinical development for the treatment of amyotrophic lateral sclerosis[J]. Expert Opin Investig Drugs, 2017, 26:403-414.
[12] Bucchia M, Ramirez A, Parente V, et al. Therapeutic develop ment in amyotrophic lateral sclerosis[J]. Clin Ther, 2015, 37:668-680.
[13] Wong PC, Pardo CA, Borchelt DR, et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria[J]. Neuron, 1995, 14:1105-1116.
[14] Bruijn LI, Becher MW, Lee MK, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions[J]. Neuron, 1997, 18:327-338.
[15] Ripps ME, Huntley GW, Hof PR, et al. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis[J]. Proc Natl Acad Sci U S A, 1995, 92:689-693.
[16] Saberi S, Stauffer JE, Schulte DJ, et al. Neuropathology of amyotrophic lateral sclerosis and its variants[J]. Neurol Clin, 2015, 33:855-876.
[17] Shibata N. Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation[J]. Neuropathology, 2001, 21:82-92.
[18] Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation[J]. Science, 1994, 264:1772-1775.
[19] Siddique T, Deng HX. Genetics of amyotrophic lateral sclerosis[J]. Hum Mol Genet, 1996, 5:1465-1470.
[20] Filali M, Lalonde R, Rivest S. Sensorimotor and cognitive functions in a SOD1G37R transgenic mouse model of amyotrophic lateral sclerosis[J]. Behav Brain Res, 2011, 225:215-221.
[21] Quarta E, Bravi R, Scambi I, et al. Increased anxiety-like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1G93A ALS mouse model[J]. J Comp Neurol, 2015, 523:1622-1638.
[22] McGoldrick P, Joyce PI, Fisher EM, et al. Rodent models of amyotrophic lateral sclerosis[J]. Biochim Biophys Acta, 2013, 1832:1421-1436.
[23] Venkova-Hristova K, Christov A, Kamaluddin Z, et al. Progress in therapy development for amyotrophic lateral sclerosis[J]. Neurol Res Int, 2012, 2012:187234.
[24] Gurney ME, Fleck TJ, Himes CS, et al. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis[J]. Neurology, 1998, 50:62-66.
[25] Ito H, Wate R, Zhang J, et al. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice[J]. Exp Neurol, 2008, 213:448-455.
[26] Juranek JK, Daffu GK, Geddis MS, et al. Soluble RAGE treat ment delays progression of amyotrophic lateral sclerosis in SOD1 mice[J]. Front Cell Neurosci, 2016, 10:117.
[27] Ozdinler PH, Benn S, Yamamoto TH, et al. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G93A transgenic ALS mice[J]. J Neurosci, 2011, 31:4166-4177.
[28] Gurney ME. The use of transgenic mouse models of amyo trophic lateral sclerosis in preclinical drug studies[J]. J Neurol Sci, 1997, 152:S67-S73.
[29] Aoki M. Amyotrophic lateral sclerosis:recent insights from transgenic animal models with SOD1 mutations[J]. Rinsho Shinkeigaku, 2004, 44:788-791.
[30] Rosser E, Grey R, Neal D, et al. Supporting clinical leadership through action:the nurse consultant role[J]. J Clin Nurs, 2017, 12:4768-4776.
[31] Indo HP, Davidson M, Yen HC, et al. Evidence of ROS genera tion by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage[J]. Mitochondrion, 2007, 7:106-118.
[32] Kaus A, Sareen D. ALS patient stem cells for unveiling disease signatures of motoneuron susceptibility:perspectives on the deadly mitochondria, ER stress and calcium triad[J]. Front Cell Neurosci, 2015, 9:448.
[33] Zhu Y, Fotinos A, Mao LL, et al. Neuroprotective agents target molecular mechanisms of disease in ALS[J]. Drug Discov Today, 2015, 20:65-75.
[34] Pellegrini-Giampietro DE, Cherici G, Alesiani M, et al. Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage[J]. J Neuro sci, 1990, 10:1035-1041.
[35] Scott S, Kranz JE, Cole J, et al. Design, power, and interpreta tion of studies in the standard murine model of ALS[J]. Amyo troph Lateral Scler, 2008, 9:4-15.
[36] Garbuzova-Davis S, Kurien C, Thomson A, et al. Endothelial and astrocytic support by human bone marrow stem cell grafts into symptomatic ALS mice towards blood-spinal cord barrier repair[J]. Sci Rep, 2017, 7:884.
[37] Mancuso R, Osta R, Navarro X. Presymptomatic electrophysio logical tests predict clinical onset and survival in SOD1G93A ALS mice[J]. Muscle Nerve, 2014, 50:943-949.
[38] Feng X, Peng Y, Liu M, et al. DL-3-n-butylphthalide extends survival by attenuating glial activation in a mouse model of amyotrophic lateral sclerosis[J]. Neuropharmacology, 2012, 62:1004-1010.
[39] Liu YC, Chiang PM, Tsai KJ. Disease animal models of TDP-43 proteinopathy and their pre-clinical applications[J]. Int J Mol Sci, 2013, 14:20079-20111.
[40] Xu YF, Zhang YJ, Lin WL, et al. Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice[J]. Mol Neuro degener, 2011, 6:73.
[41] Arnold ES, Ling SC, Huelga SC, et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43[J]. Proc Natl Acad Sci U S A, 2013, 110:E736-E745.
[42] Swarup V, Phaneuf D, Bareil C, et al. Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments[J]. Brain, 2011, 134:2610-2626.
[43] Hatzipetros T, Bogdanik LP, Tassinari VR, et al. C57BL/6J congenic Prp-TDP-43A315T mice develop progressive neuro degeneration in the myenteric plexus of the colon without exhibiting key features of ALS[J]. Brain Res, 2014, 1584:59-72.
[44] Huang C, Tong J, Bi F, et al. Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats[J]. J Clin Invest, 2012, 122:107-118.
[45] Wegorzewska I, Bell S, Cairns NJ, et al. TDP-43 mutant trans genic mice develop features of ALS and frontotemporal lobar degeneration[J]. Proc Natl Acad Sci U S A, 2009, 106:18809-18814.
[46] Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis[J]. Nat Genet, 2008, 40:572-574.
[47] Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis[J]. Science, 2006, 314:130-133.
[48] Blokhuis AM, Groen EJ, Koppers M, et al. Protein aggregation in amyotrophic lateral sclerosis[J]. Acta Neuropathol, 2013, 125:777-794.
[49] Crozat A, Aman P, Mandahl N, et al. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma[J]. Nature, 1993, 363:640-644.
[50] Gal J, Zhang J, Kwinter DM, et al. Nuclear localization sequence of FUS and induction of stress granules by ALS mutants[J]. Neurobiol Aging, 2011, 32:2323. e27-40.
[51] Nolan M, Talbot K, Ansorge O. Pathogenesis of FUS-associated ALS and FTD:insights from rodent models[J]. Acta Neuro pathol Commun, 2016, 4:99.
[52] Sharma A, Lyashchenko AK, Lu L, et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function[J]. Nat Commun, 2016, 7:10465.
[53] Shelkovnikova TA, Peters OM, Deykin AV, et al. Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice[J]. J Biol Chem, 2013, 288:25266-25274.
[54] Rabouille C, Alberti S. Cell adaptation upon stress:the emerging role of membrane-less compartments[J]. Curr Opin Cell Biol, 2017, 47:34-42.
[55] Ramaswami M, Taylor JP, Parker R. Altered ribostasis:RNAprotein granules in degenerative disorders[J]. Cell, 2013, 154:727-736.
[56] Ittner LM, Halliday GM, Kril JJ, et al. FTD and ALS——translating mouse studies into clinical trials[J]. Nat Rev Neurol, 2015, 11:360-366.
[57] Koppers M, Blokhuis AM, Westeneng HJ, et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits[J]. Ann Neurol, 2015, 78:426-438.
[58] Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD:multiple pathways to disease[J]. Nat Rev Neurol, 2018, 14:544-558.
[59] Moens TG, Partridge L, Isaacs AM. Genetic models of C9orf72:what is toxic?[J]. Curr Opin Genet Dev, 2017, 44:92-101.
[60] Lee EB, Lee VM, Trojanowski JQ. Gains or losses:molecular mechanisms of TDP43-mediated neurodegeneration[J]. Nat Rev Neurosci, 2011, 13:38-50.
[61] Iguchi Y, Katsuno M, Niwa J, et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration[J]. Brain, 2013, 136:1371-1382.
[62] Boillee S, Peschanski M, Junier MP. The wobbler mouse:a neurodegeneration jigsaw puzzle[J]. Mol Neurobiol, 2003, 28:65-106.
[63] Pioro EP, Mitsumoto H. Animal models of ALS[J]. Clin Neurosci, 1995, 3:375-385.
[64] Resch K, Korthaus D, Wedemeyer N, et al. Homology between human chromosome 2p13.3 and the wobbler critical region on mouse chromosome 11:comparative high-resolution mapping of STS and EST loci on YAC/BAC contigs[J]. Mamm Genome, 1998, 9:893-898.
[65] Dave KR, Bradley WG, Perez-Pinzon MA. Early mitochondrial dysfunction occurs in motor cortex and spinal cord at the onset of disease in the Wobbler mouse[J]. Exp Neurol, 2003, 182:412-420.
[66] Ludolph AC, Bendotti C, Blaugrund E, et al. Guidelines for preclinical animal research in ALS/MND:a consensus meeting[J]. Amyotroph Lateral Scler, 2010, 11:38-45.
[67] Dal Canto MC, Gurney ME. Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu, Zn SOD, and in mice overexpressing wild type human SOD:a model of familial amyotrophic lateral sclerosis (FALS)[J]. Brain Res, 1995, 676:25-40.
[68] Dal Canto MC, Gurney ME. A low expressor line of transgenic mice carrying a mutant human Cu, Zn superoxide dismutase (SOD1) gene develops pathological changes that most closely resemble those in human amyotrophic lateral sclerosis[J]. Acta Neuropathol, 1997, 93:537-550.
[69] Matus S, Medinas DB, Hetz C. Common ground:stem cell approaches find shared pathways underlying ALS[J]. Cell Stem Cell, 2014, 14:697-699.
[70] Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy[J]. Nature, 2012, 481:295-305.
[71] Myszczynska M, Ferraiuolo L. New in vitro models to study amyotrophic lateral sclerosis[J]. Brain Pathol, 2016, 26:258-265.
[72] Yang S, He R, Zhang FY, et al. Application of cell co-culture techniques in central nervous system diseases[J]. Acta Pharm Sin (药学学报), 2016, 51:338-346.