肌萎缩侧索硬化的药物治疗进展
摘要
肌萎缩侧索硬化(Amyotrophic lateral sclerosis , ALS)是一种成年起病的神经系统变性疾病,其发病机制并不清楚。大约20%的家族性ALS有铜/锌超氧化物歧化酶(Cu /Zn superoxide dismutase, SOD1)基因突变。目前,没有有效的治疗方法,然而研究ALS药物治疗的试验有显著增加,已经开展了一些重要的临床实验和应用SOD1转基因小鼠的动物试验。为此,我们对近年来有关ALS药物治疗的研究结果进行了综述,供研究者和临床医生参考。近期研究表明减少星形胶质细胞中SOD1突变基因的表达,可延缓疾病的进展,它是目前基因治疗的靶标。并且,已经在家族性ALS患者体内发现了变异的43-kDa TAR基因相关蛋白(TDP-43),这是对ALS发病机制的极大补充。抗兴奋性谷氨酸毒性药物对ALS患者有保护作用。多亚型的谷氨酸受体为寻找高效、安全的新药提供了有益的靶标。例如利鲁唑,它是目前惟一通过美国食品与药品管理局(FDA)认定对ALS确实有效的药物,但其只能延缓ALS的病程。虽然神经营养因子IGF-1在III期临床试验中无明显疗效,但人重组肝细胞生长因子、人重组促红细胞生长因子、粒细胞集落刺激因子在SOD1动物模型实验中取得了可喜的成果。抗氧化和改善线粒体功能的药物正处于研究阶段,应激调节能够为神经细胞变性提供保护作用。神经干细胞移植是近年来研究的热点。在一项研究中,病人骨髓间质干细胞注入转基因小鼠蛛网膜下腔中取得了一定的疗效。
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. The mechanisms underlying selective motor neuron degeneration in ALS remain unknown. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. There is no curative treatment for ALS. Nevertheless, there is an increasing volume of published studies. There have been several important clinical trials on the treatment of ALS and treatment efficacy studies using mouse (SOD1) models of ALS. This review assesses the current evidence for treatment of ALS,which provide reference to investigator and clinician. Recent studies revealed that diminished mutant SOD1 expression in the astrocytes delayed microglial activation and slowed disease progression. It can be target of the gene therapy. Current evidence has implicated a 43-kDa TAR DNA-binding protein (TDP-43) in the pathologenesis of ALS. Several mutations in TDP-43 were discovered in families with inherited motor neuron disease. It is a complementarity for the mechanism of ALS. Antiglutamate toxicity has been reported to have a protective effect on ALS patients,which attribute to multiple glutamate receptors. For example riluzole, which is the only drug for the treatment of ALS approved by the Food and Drug Administration,but with only modest increase in survival. Although phase III trials revealed that IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with hepatocyte growth factor(hrHGF)、recombinant human erythropoietin (rhEPO)、the granulocyte colony stimulating factor (G-CSF). Administrations of antioxidant、amending mitochondrial function have been investigated. A conditioning lesion provides selective protection in a rat model of ALS. This years, transplantation of neural stem cells is hotspot of investigation.In a study, ALS-human mesenchymal stem cells were transplanted into cisterna magna in SOD1-G93A ALS mice,it is a potential route for stem cell therapy in ALS patients.
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. The mechanisms underlying selective motor neuron degeneration in ALS remain unknown. Approximately 20% of familial ALS cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene. There is no curative treatment for ALS. Nevertheless, there is an increasing volume of published studies. There have been several important clinical trials on the treatment of ALS and treatment efficacy studies using mouse (SOD1) models of ALS. This review assesses the current evidence for treatment of ALS,which provide reference to investigator and clinician. Recent studies revealed that diminished mutant SOD1 expression in the astrocytes delayed microglial activation and slowed disease progression. It can be target of the gene therapy. Current evidence has implicated a 43-kDa TAR DNA-binding protein (TDP-43) in the pathologenesis of ALS. Several mutations in TDP-43 were discovered in families with inherited motor neuron disease. It is a complementarity for the mechanism of ALS. Antiglutamate toxicity has been reported to have a protective effect on ALS patients,which attribute to multiple glutamate receptors. For example riluzole, which is the only drug for the treatment of ALS approved by the Food and Drug Administration,but with only modest increase in survival. Although phase III trials revealed that IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with hepatocyte growth factor(hrHGF)、recombinant human erythropoietin (rhEPO)、the granulocyte colony stimulating factor (G-CSF). Administrations of antioxidant、amending mitochondrial function have been investigated. A conditioning lesion provides selective protection in a rat model of ALS. This years, transplantation of neural stem cells is hotspot of investigation.In a study, ALS-human mesenchymal stem cells were transplanted into cisterna magna in SOD1-G93A ALS mice,it is a potential route for stem cell therapy in ALS patients.
引文
1 Miller RG, et al Practice parameter update: The care of the patient with amyotrophic lateral sclerosis -Drug, nutritional, and respiratory therapies (an evidence-based review). Quality Standards Subcommittee of the American Academy of Neurology,2009, 13(73):1218
2李晓光,崔丽英,刘明生,国际肌萎缩侧索硬化临床实践指南解读。中国实用内科杂志,2009,29(2):114—116
3 World Federation of Neurology Research Group on Neuromuscular Diseases Subcommittee on Motor Neuron Disease. Airlie House guidelines. Therapeutic trials in amyotrophic lateral sclerosis. Airlie House "Therapeutic Trials in ALS" Workshop Contributors.J Neurol Sci, 1995 ,129( Suppl):1-10
4 Miller RG, Mitchell JD, Lyon M ,Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral SclerOther Motor Neuron Disord, 2003,4(3):191-206
5 Pascuzzi RM, Shefner J, Chappell AS, A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. talampanel Amyotroph Lateral Scler, 2009,post on line 0(0):1-6
6 hazzini L, et al ALS defeats gabapentin:reflection on another failed treatment. J NEURO Sci, 1998; 160(suppl 1):s57
7黄慧,肌萎缩侧索硬化症药物治疗的研究进展。国际神经病学神经外科学杂志,2006,33(4):322-326
8 Howe CL, Bergstrom RA, Horazdovsky BF, Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology,2009,73(15): 1247-8
9 Aoki M, Warita H, Suzuki N,Development of motor neuron restorative therapy in amyotrophic lateral sclerosis using hepatocyte growth factor.Rinsho Shinkeigaku, 2009,49(11):814-7
10 Lauria G, Campanella A, Filippini G, Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability. Amyotroph Lateral Scler, 2009,10(5-6):410-5
11 Zhang Y, Wang L, Fu Y, Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis. Neurology,2009;10(5-6):430-1
12 Gordon PH, Moore DH, Miller RG, Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol, 2007,6(12):1045-53
13 Rosenfeld J,King RM,Jackson CE,et a1 Creatine monohydrate in ALs: efects Oil strength, fatigue, respiratory status and ALSFRS.Amyotropb Lateral Scler,2008,9:266-272
14 Henderson JT,Javaheri M,Kopko S,et a1 Reduofionof lower motor neuron degeneration in wobbler mice by N·acetyl·L—eysteine . J Neurosci,1996,16(23):7574—7582
15 Andressen OA,Dedeoqlu A,Klibenyi P,et a1 Nacetyl-L--cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.Neuroreport,2000,11(11):2491-2493
16 Desnuelle C,Dib M,Garrel C,et a1 A double—blind,placebo- -controlled randomized clinical trial of alpha--toeopherol vitaminE in the treatment of amyotrophic lateral sclerosis: ALS riluzole—tocopherol Study Group.Amyotroph Latral SclerOther Motor Neuron Disord,2001,2(1):9—18
17 Levy G,Kaufmann P,Buchsbaum R,et a1 A two—stage designfor a phase I1 clinical trial of coenzyme Q10 in ALS.Neurology, 2006,66:660-663
18李晓光,郭玉璞,肌萎缩侧索硬化诊断及治疗。脑与神经疾病杂志,2000 ,8 (4) :126-128
19 Miller RG, Examing the evidence about treatment in ALS/ MND . Amyotroph Lateral Scler Other Motor Neuron Disord ,2001 ,2 (1) :327
20 Swash M, ALS 2000 :the past points to the future. AmyotrophLateral Scler Other Motor Neuron Disord ,2001 ,2 (Suppl) :329
21 Sargsyan SA,Monk PN,Shaw PJ,Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis .Glia,2005,51(4):241—253
22 Franz CK, Quach ET, Krudy CA, A conditioning lesion provides selective protection in a rat model of Amyotrophic Lateral Sclerosis. PLoS One, 2009,4(10):e7357
23 Lanka V, Wieland S, Barber J, Arimoclomol: a potential therapy under development for ALS. Expert Opin Investig Drugs,2009,18(12):1907-18
24 Rinsho Shinkeigaku, RNAi applications in therapy development for neurodegenerative disease. Curr Pharm Des, 2009,49(11):821-3
25 Hester ME, Foust KD, Kaspar RW, AAV as a gene transfer vector for the treatment of neurological disorders: novel treatment thoughts for ALS. Curr Gene Ther,2009,9(5):428-33
26 Moreno-Igoa M, Calvo AC, Penas C, Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. J Mol Med, 2010,88(3):297-308
27 Kabashi, Li Lin, Miranda L, Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo .Human Molecular Genetics ,2010, 19(4):671-683
28安沂华,程洪斌,张儒有,神经干细胞临床应用和前景展望。内科急危重症杂志,2005,11(5):238-9
29 Kim H, Kim HY, Choi MR, Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett,2010,468(3):190-4
30王继明,吴以岭,杨萍,陈金亮,周顺林,马文龙,原代培养鼠胚脊髓运动神经元活力状态与肌萎灵注射液的干预作用,中国组织工程研究与临床康复,2007,11(14):2676-2679
31陈金亮,平阳,王殿华.肌萎灵系列制剂治疗肌萎缩侧索硬化症240例疗效观察。新中医,2005,37(9):38-39
32王继明,吴以岭,陈金亮,肌萎灵注射液对人骨髓基质细胞增殖和向神经细胞分化的影响。中国中医基础医学杂志,2007,13(10):768-770
33孙华,崔丽英,针灸治疗运动神经元病的现状。中国临床康复,2005,9(21):174-175
34 Suh Young Jeong, Khizr I, Rathore, Katrin Schulz, Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis. The Journal of Neuroscience,January 21, 2009, 29(3):610-619
35 Ferrucci M, Spalloni A, Bartalucci A, A systematic study of brainstem motor nuclei in a mouse model of ALS. the effects of lithium. Neurobiol Dis, 2010 ,37(2):370-83
1吴江,贾建平,崔丽英,神经病学,人民卫生出版社,2005年8月第一版,341-343
2姬文珍,杨丽,何伯永,重症肌无力与甲状腺疾病的共患研究。《临床荟萃》,2009,24(2):182-184
3 Mappouras DG,Philippou G, Haralambous S ,et al , Antibodies to acetlcholinsterase cross-reating with thyroglobulin in myasthenia gravis and Graves’disease . Clm Exp Immunol , 1995 ,100 (2) :336-343
4 Tanwani L K, Lohano V , Ewart R, Myast henia gravis inconjunction with Graves’disease : a diagnostic challenge . Endocr Pract ,2001,7(4):275-278
5陆去强,胡予,杨永年,等,甲状腺功能亢进症。12版.实用内科学,北京:人民卫生出版社,2005:1231-1245
6潘铁成,杨明山,胸腺疾病。北京:人民卫生出版社,2002:134–170
7 Bedlack RS, Sanders DB, Steroid treatment formyasthenia.gravis: steroids have an important role. Muscle Nerve,2002;25(1):117–121
8孙英晶,糖皮质激素为主综合治疗重症肌无力的临床观察。内蒙古中医药,2009,6:64-65
9范伟女,洪文轲,环磷酰胺或硫唑嘌呤对耐受糖皮质激素重症肌无力的疗效观察。现代实用医学,2009,21(5),463-465
10张爱萍,健康教育对重症肌无力病人遵医行为的干预。全科护理,2009,7(1):275-276
11李海峰,孙运波,丛志强,重症肌无力患者呼吸衰竭的早期识别和处理。中华急诊医学杂志,2004,13(5):359-360
13马颖娟,37例重症肌无力患者的护理。中国实用神经疾病杂志,2009,12(4):66-67
2李晓光,崔丽英,刘明生,国际肌萎缩侧索硬化临床实践指南解读。中国实用内科杂志,2009,29(2):114—116
3 World Federation of Neurology Research Group on Neuromuscular Diseases Subcommittee on Motor Neuron Disease. Airlie House guidelines. Therapeutic trials in amyotrophic lateral sclerosis. Airlie House "Therapeutic Trials in ALS" Workshop Contributors.J Neurol Sci, 1995 ,129( Suppl):1-10
4 Miller RG, Mitchell JD, Lyon M ,Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral SclerOther Motor Neuron Disord, 2003,4(3):191-206
5 Pascuzzi RM, Shefner J, Chappell AS, A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. talampanel Amyotroph Lateral Scler, 2009,post on line 0(0):1-6
6 hazzini L, et al ALS defeats gabapentin:reflection on another failed treatment. J NEURO Sci, 1998; 160(suppl 1):s57
7黄慧,肌萎缩侧索硬化症药物治疗的研究进展。国际神经病学神经外科学杂志,2006,33(4):322-326
8 Howe CL, Bergstrom RA, Horazdovsky BF, Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology,2009,73(15): 1247-8
9 Aoki M, Warita H, Suzuki N,Development of motor neuron restorative therapy in amyotrophic lateral sclerosis using hepatocyte growth factor.Rinsho Shinkeigaku, 2009,49(11):814-7
10 Lauria G, Campanella A, Filippini G, Erythropoietin in amyotrophic lateral sclerosis: a pilot, randomized, double-blind, placebo-controlled study of safety and tolerability. Amyotroph Lateral Scler, 2009,10(5-6):410-5
11 Zhang Y, Wang L, Fu Y, Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis. Neurology,2009;10(5-6):430-1
12 Gordon PH, Moore DH, Miller RG, Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol, 2007,6(12):1045-53
13 Rosenfeld J,King RM,Jackson CE,et a1 Creatine monohydrate in ALs: efects Oil strength, fatigue, respiratory status and ALSFRS.Amyotropb Lateral Scler,2008,9:266-272
14 Henderson JT,Javaheri M,Kopko S,et a1 Reduofionof lower motor neuron degeneration in wobbler mice by N·acetyl·L—eysteine . J Neurosci,1996,16(23):7574—7582
15 Andressen OA,Dedeoqlu A,Klibenyi P,et a1 Nacetyl-L--cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.Neuroreport,2000,11(11):2491-2493
16 Desnuelle C,Dib M,Garrel C,et a1 A double—blind,placebo- -controlled randomized clinical trial of alpha--toeopherol vitaminE in the treatment of amyotrophic lateral sclerosis: ALS riluzole—tocopherol Study Group.Amyotroph Latral SclerOther Motor Neuron Disord,2001,2(1):9—18
17 Levy G,Kaufmann P,Buchsbaum R,et a1 A two—stage designfor a phase I1 clinical trial of coenzyme Q10 in ALS.Neurology, 2006,66:660-663
18李晓光,郭玉璞,肌萎缩侧索硬化诊断及治疗。脑与神经疾病杂志,2000 ,8 (4) :126-128
19 Miller RG, Examing the evidence about treatment in ALS/ MND . Amyotroph Lateral Scler Other Motor Neuron Disord ,2001 ,2 (1) :327
20 Swash M, ALS 2000 :the past points to the future. AmyotrophLateral Scler Other Motor Neuron Disord ,2001 ,2 (Suppl) :329
21 Sargsyan SA,Monk PN,Shaw PJ,Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis .Glia,2005,51(4):241—253
22 Franz CK, Quach ET, Krudy CA, A conditioning lesion provides selective protection in a rat model of Amyotrophic Lateral Sclerosis. PLoS One, 2009,4(10):e7357
23 Lanka V, Wieland S, Barber J, Arimoclomol: a potential therapy under development for ALS. Expert Opin Investig Drugs,2009,18(12):1907-18
24 Rinsho Shinkeigaku, RNAi applications in therapy development for neurodegenerative disease. Curr Pharm Des, 2009,49(11):821-3
25 Hester ME, Foust KD, Kaspar RW, AAV as a gene transfer vector for the treatment of neurological disorders: novel treatment thoughts for ALS. Curr Gene Ther,2009,9(5):428-33
26 Moreno-Igoa M, Calvo AC, Penas C, Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. J Mol Med, 2010,88(3):297-308
27 Kabashi, Li Lin, Miranda L, Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo .Human Molecular Genetics ,2010, 19(4):671-683
28安沂华,程洪斌,张儒有,神经干细胞临床应用和前景展望。内科急危重症杂志,2005,11(5):238-9
29 Kim H, Kim HY, Choi MR, Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett,2010,468(3):190-4
30王继明,吴以岭,杨萍,陈金亮,周顺林,马文龙,原代培养鼠胚脊髓运动神经元活力状态与肌萎灵注射液的干预作用,中国组织工程研究与临床康复,2007,11(14):2676-2679
31陈金亮,平阳,王殿华.肌萎灵系列制剂治疗肌萎缩侧索硬化症240例疗效观察。新中医,2005,37(9):38-39
32王继明,吴以岭,陈金亮,肌萎灵注射液对人骨髓基质细胞增殖和向神经细胞分化的影响。中国中医基础医学杂志,2007,13(10):768-770
33孙华,崔丽英,针灸治疗运动神经元病的现状。中国临床康复,2005,9(21):174-175
34 Suh Young Jeong, Khizr I, Rathore, Katrin Schulz, Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis. The Journal of Neuroscience,January 21, 2009, 29(3):610-619
35 Ferrucci M, Spalloni A, Bartalucci A, A systematic study of brainstem motor nuclei in a mouse model of ALS. the effects of lithium. Neurobiol Dis, 2010 ,37(2):370-83
1吴江,贾建平,崔丽英,神经病学,人民卫生出版社,2005年8月第一版,341-343
2姬文珍,杨丽,何伯永,重症肌无力与甲状腺疾病的共患研究。《临床荟萃》,2009,24(2):182-184
3 Mappouras DG,Philippou G, Haralambous S ,et al , Antibodies to acetlcholinsterase cross-reating with thyroglobulin in myasthenia gravis and Graves’disease . Clm Exp Immunol , 1995 ,100 (2) :336-343
4 Tanwani L K, Lohano V , Ewart R, Myast henia gravis inconjunction with Graves’disease : a diagnostic challenge . Endocr Pract ,2001,7(4):275-278
5陆去强,胡予,杨永年,等,甲状腺功能亢进症。12版.实用内科学,北京:人民卫生出版社,2005:1231-1245
6潘铁成,杨明山,胸腺疾病。北京:人民卫生出版社,2002:134–170
7 Bedlack RS, Sanders DB, Steroid treatment formyasthenia.gravis: steroids have an important role. Muscle Nerve,2002;25(1):117–121
8孙英晶,糖皮质激素为主综合治疗重症肌无力的临床观察。内蒙古中医药,2009,6:64-65
9范伟女,洪文轲,环磷酰胺或硫唑嘌呤对耐受糖皮质激素重症肌无力的疗效观察。现代实用医学,2009,21(5),463-465
10张爱萍,健康教育对重症肌无力病人遵医行为的干预。全科护理,2009,7(1):275-276
11李海峰,孙运波,丛志强,重症肌无力患者呼吸衰竭的早期识别和处理。中华急诊医学杂志,2004,13(5):359-360
13马颖娟,37例重症肌无力患者的护理。中国实用神经疾病杂志,2009,12(4):66-67