Safety of intrathecal injection of Wharton's jellyderived mesenchymal stem cells in amyotrophic lateral sclerosis therapy
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摘要
Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.
Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.
Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.
引文
Andersen PM,Al-Chalabi A(2011)Clinical genetics of amyotrophic lateral sclerosis:what do we really know?Nat Rev Neurol 7:603-615.
Beers DR,Henkel JS,Zhao W,Wang J,Huang A,Wen S,Liao B,Appel SH(2011)Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.Brain134:1293-1314.
Beers DR,Zhao W,Wang J,Zhang X,Wen S,Neal D,Thonhoff JR,Alsuliman AS,Shpall EJ,Rezvani K,Appel SH(2017)ALS patients’regulatory T lymphocytes are dysfunctional,and correlate with disease progression rate and severity.JCI Insight 2:e89530.
Bensimon G,Lacomblez L,Meininger V(1994)A controlled trial of riluzole in amyotrophic lateral sclerosis.ALS/Riluzole Study Group.N Engl J Med 330:585-591.
Blondheim NR,Levy YS,Ben-Zur T,Burshtein A,Cherlow T,Kan I,Barzilai R,Bahat-Stromza M,Barhum Y,Bulvik S,Melamed E,Offen D(2006)Human mesenchymal stem cells express neural genes,suggesting a neural predisposition.Stem Cells Dev 15:141-164.
Brooks BR(1994)El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis.Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial“Clinical limits of amyotrophic lateral sclerosis”workshop contributors.J Neurol Sci 124 Suppl:96-107.
Brooks BR,Miller RG,Swash M,Munsat TL,World Federation of Neurology Research Group on Motor Neuron D(2000)El Escorial revisited:revised criteria for the diagnosis of amyotrophic lateral sclerosis.Amyotroph Lateral Scler Other Motor Neuron Disord 1:293-299.
Chen G,Yue A,Ruan Z,Yin Y,Wang R,Ren Y,Zhu L(2014)Monitoring the biology stability of human umbilical cord-derived mesenchymal stem cells during long-term culture in serum-free medium.Cell Tissue Bank 15:513-521.
Chio A,Logroscino G,Traynor BJ,Collins J,Simeone JC,Goldstein LA,White LA(2013)Global epidemiology of amyotrophic lateral sclerosis:a systematic review of the published literature.Neuroepidemiology 41:118-130.
Cui F,Cai W,Wang Z,Ren Y,Li M,Sun Z,Huang X(2013)New mutation in the SOD1(copper/zinc superoxide dismutase-1)gene in a Chinese amyotrophic lateral sclerosis(ALS)patient.Amyotroph Lateral Scler Frontotemporal Degener 14:635-637.
Czarzasta J,Habich A,Siwek T,Czaplinski A,Maksymowicz W,Wojtkiewicz J(2017)Stem cells for ALS:An overview of possible therapeutic approaches.Int J Dev Neurosci 57:46-55.
Fecto F,Yan J,Vemula SP,Liu E,Yang Y,Chen W,Zheng JG,Shi Y,Siddique N,Arrat H,Donkervoort S,Ajroud-Driss S,Sufit RL,Heller SL,Deng HX,Siddique T(2011)SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.Arch Neurol 68:1440-1446.
Forostyak S,Sykova E(2017)Neuroprotective potential of cell-based therapies in ALS:from bench to bedside.Front Neurosci 11:591.
Frausin S,Viventi S,Verga Falzacappa L,Quattromani MJ,Leanza G,Tommasini A,Valencic E(2015)Wharton’s jelly derived mesenchymal stromal cells:Biological properties,induction of neuronal phenotype and current applications in neurodegeneration research.Acta Histochem 117:329-338.
Ge W,Ren C,Duan X,Geng D,Zhang C,Liu X,Chen H,Wan M,Geng R(2015)Differentiation of mesenchymal stem cells into neural stem cells using cerebrospinal fluid.Cell Biochem Biophys71:449-455.
Gordon PH(2011)Amyotrophic lateral sclerosis:pathophysiology,diagnosis and management.CNS Drugs 25:1-15.
Goutman SA(2017)Diagnosis and Clinical management of amyotrophic lateral sclerosis and other motor neuron disorders.Continuum(Minneap Minn)23:1332-1359.
Hass R,Kasper C,Bohm S,Jacobs R(2011)Different populations and sources of human mesenchymal stem cells(MSC):A comparison of adult and neonatal tissue-derived MSC.Cell Commun Signal 9:12.
Henkel JS,Beers DR,Zhao W,Appel SH(2009)Microglia in ALS:the good,the bad,and the resting.J Neuroimmune Pharmacol 4:389-398.
Jablecki CK,Berry C,Leach J(1989)Survival prediction in amyotrophic lateral sclerosis.Muscle Nerve 12:833-841.
Jaiswal MK(2018)Riluzole and edaravone:A tale of two amyotrophic lateral sclerosis drugs.Med Res Rev.
Kalaszczynska I,Ferdyn K(2015)Wharton’s jelly derived mesenchymal stem cells:future of regenerative medicine?Recent findings and clinical significance.Biomed Res Int 2015:430847.
Kano O,Iwamoto K,Ito H,Kawase Y,Cridebring D,Ikeda K,Iwasaki Y(2013)Limb-onset amyotrophic lateral sclerosis patients visiting orthopedist show a longer time-to-diagnosis since symptom onset.BMC Neurol 13:19.
Kikuchi K,Takeshige N,Miura N,Morimoto Y,Ito T,Tancharoen S,Miyata K,Kikuchi C,Iida N,Uchikado H,Miyagi N,Shiomi N,Kuramoto T,Maruyama I,Morioka M,Kawahara KI(2012)Beyond free radical scavenging:Beneficial effects of edaravone(Radicut)in various diseases(Review).Exp Ther Med 3:3-8.
Kwon MS,Noh MY,Oh KW,Cho KA,Kang BY,Kim KS,Kim YS,Kim SH(2014)The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALSpatients.J Neurochem 131:206-218.
Lewis KE,Rasmussen AL,Bennett W,King A,West AK,Chung RS,Chuah MI(2014)Microglia and motor neurons during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis:changes in arginase1 and inducible nitric oxide synthase.JNeuroinflammation 11:55.
Logroscino G,Traynor BJ,Hardiman O,Chio A,Couratier P,Mitchell JD,Swingler RJ,Beghi E,Eurals(2008)Descriptive epidemiology of amyotrophic lateral sclerosis:new evidence and unsolved issues.J Neurol Neurosurg Psychiatry 79:6-11.
Marconi S,Bonaconsa M,Scambi I,Squintani GM,Rui W,Turano E,Ungaro D,D’Agostino S,Barbieri F,Angiari S,Farinazzo A,Constantin G,Del Carro U,Bonetti B,Mariotti R(2013)Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model.Neuroscience 248:333-343.
Mazzini L,Fagioli F,Boccaletti R,Mareschi K,Oliveri G,Olivieri C,Pastore I,Marasso R,Madon E(2003)Stem cell therapy in amyotrophic lateral sclerosis:a methodological approach in humans.Amyotroph Lateral Scler Other Motor Neuron Disord 4:158-161.
Mazzini L,Mareschi K,Ferrero I,Vassallo E,Oliveri G,Boccaletti R,Testa L,Livigni S,Fagioli F(2006)Autologous mesenchymal stem cells:clinical applications in amyotrophic lateral sclerosis.Neurol Res 28:523-526.
Mazzini L,Mareschi K,Ferrero I,Miglioretti M,Stecco A,Servo S,Carriero A,Monaco F,Fagioli F(2012)Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis:a long-term safety study.Cytotherapy 14:56-60.
Mazzini L,Ferrero I,Luparello V,Rustichelli D,Gunetti M,Mareschi K,Testa L,Stecco A,Tarletti R,Miglioretti M,Fava E,Nasuelli N,Cisari C,Massara M,Vercelli R,Oggioni GD,Carriero A,Cantello R,Monaco F,Fagioli F(2010)Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis:a phase I clinical trial.Exp Neurol223:229-237.
Miller RG,Mitchell JD,Lyon M,Moore DH(2007)Riluzole for amyotrophic lateral sclerosis(ALS)/motor neuron disease(MND).Cochrane Database Syst Rev:CD001447.
Mora JS(2017)Edaravone for treatment of early-stage ALS.Lancet Neurol 16:772.
Morgan S,Orrell RW(2016)Pathogenesis of amyotrophic lateral sclerosis.Br Med Bull 119:87-98.
Moujalled D,White AR(2016)Advances in the development of disease-modifying treatments for amyotrophic lateral sclerosis.CNSDrugs 30:227-243.
Oh KW,Moon C,Kim HY,Oh SI,Park J,Lee JH,Chang IY,Kim KS,Kim SH(2015)Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis.Stem Cells Transl Med 4:590-597.
Petrou P,Gothelf Y,Argov Z,Gotkine M,Levy YS,Kassis I,Vaknin-Dembinsky A,Ben-Hur T,Offen D,Abramsky O,Melamed E,Karussis D(2016)Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis:results of phase 1/2 and 2a clinical trials.JAMA Neurol 73:337-344.
Petrov D,Mansfield C,Moussy A,Hermine O(2017)ALS clinical trials review:20 years of failure.Are we any closer to registering a new treatment?Front Aging Neurosci 9:68.
Prabhakar S,Marwaha N,Lal V,Sharma RR,Rajan R,Khandelwal N(2012)Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis:a pilot study.Neurol India 60:465-469.
Renton AE,Chio A,Traynor BJ(2014)State of play in amyotrophic lateral sclerosis genetics.Nat Neurosci 17:17-23.
Rosen DR,Siddique T,Patterson D,Figlewicz DA,Sapp P,Hentati A,Donaldson D,Goto J,O’Regan JP,Deng HX,et al.(1993)Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature 362:59-62.
Rosenbohm A,Liu M,Nagel G,Peter RS,Cui B,Li X,Kassubek J,Rothenbacher D,Lule D,Cui L,Ludolph AC,Group ALSRSS(2018)Phenotypic differences of amyotrophic lateral sclerosis(ALS)in China and Germany.J Neurol 265:774-782.
Rothstein JD(2017)Edaravone:A new drug approved for ALS.Cell171:725.
Rowland LP,Shneider NA(2001)Amyotrophic lateral sclerosis.NEngl J Med 344:1688-1700.
Rushkevich YN,Kosmacheva SM,Zabrodets GV,Ignatenko SI,Goncharova NV,Severin IN,Likhachev SA,Potapnev MP(2015)The use of autologous mesenchymal stem cells for cell therapy of patients with amyotrophic lateral sclerosis in belarus.Bull Exp Biol Med 159:576-581.
Sharma AK,Sane HM,Paranjape AA,Gokulchandran N,Nagrajan A,D’sa M,Badhe PB(2015)The effect of autologous bone marrow mononuclear cell transplantation on the survival duration in Amyotrophic Lateral Sclerosis-a retrospective controlled study.Am JStem Cells 4:50-65.
Siddique T,Figlewicz DA,Pericak-Vance MA,Haines JL,Rouleau G,Jeffers AJ,Sapp P,Hung WY,Bebout J,McKenna-Yasek D,et al.(1991)Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity.N Engl J Med 324:1381-1384.
Stifani N(2014)Motor neurons and the generation of spinal motor neuron diversity.Front Cell Neurosci 8:293.
Struys T,Moreels M,Martens W,Donders R,Wolfs E,Lambrichts I(2011)Ultrastructural and immunocytochemical analysis of multilineage differentiated human dental pulp-and umbilical cord-derived mesenchymal stem cells.Cells Tissues Organs 193:366-378.
Sun H,Sun C,Xiao W(2014)Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations.Cytokine 65:33-41.
Tada S,Okuno T,Yasui T,Nakatsuji Y,Sugimoto T,Kikutani H,Sakoda S(2011)Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis.J Neuroinflammation 8:19.
Tang Y,Le W(2016)Differential roles of M1 and m2 Microglia in neurodegenerative diseases.Mol Neurobiol 53:1181-1194.
Thonhoff JR,Beers DR,Zhao W,Pleitez M,Simpson EP,Berry JD,Cudkowicz ME,Appel SH(2018)Expanded autologous regulatory T-lymphocyte infusions in ALS:A phase I,first-in-human study.Neurol Neuroimmunol Neuroinflamm 5:e465.
Turner MR,Hardiman O,Benatar M,Brooks BR,Chio A,de Carvalho M,Ince PG,Lin C,Miller RG,Mitsumoto H,Nicholson G,Ravits J,Shaw PJ,Swash M,Talbot K,Traynor BJ,Van den Berg LH,Veldink JH,Vucic S,Kiernan MC(2013)Controversies and priorities in amyotrophic lateral sclerosis.Lancet Neurol 12:310-322.
Writing G,Edaravone ALSSG(2017)Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis:a randomised,double-blind,placebo-controlled trial.Lancet Neurol16:505-512.
Zhao W,Xie W,Xiao Q,Beers DR,Appel SH(2006)Protective effects of an anti-inflammatory cytokine,interleukin-4,on motoneuron toxicity induced by activated microglia.J Neurochem 99:1176-1187.
Beers DR,Henkel JS,Zhao W,Wang J,Huang A,Wen S,Liao B,Appel SH(2011)Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.Brain134:1293-1314.
Beers DR,Zhao W,Wang J,Zhang X,Wen S,Neal D,Thonhoff JR,Alsuliman AS,Shpall EJ,Rezvani K,Appel SH(2017)ALS patients’regulatory T lymphocytes are dysfunctional,and correlate with disease progression rate and severity.JCI Insight 2:e89530.
Bensimon G,Lacomblez L,Meininger V(1994)A controlled trial of riluzole in amyotrophic lateral sclerosis.ALS/Riluzole Study Group.N Engl J Med 330:585-591.
Blondheim NR,Levy YS,Ben-Zur T,Burshtein A,Cherlow T,Kan I,Barzilai R,Bahat-Stromza M,Barhum Y,Bulvik S,Melamed E,Offen D(2006)Human mesenchymal stem cells express neural genes,suggesting a neural predisposition.Stem Cells Dev 15:141-164.
Brooks BR(1994)El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis.Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial“Clinical limits of amyotrophic lateral sclerosis”workshop contributors.J Neurol Sci 124 Suppl:96-107.
Brooks BR,Miller RG,Swash M,Munsat TL,World Federation of Neurology Research Group on Motor Neuron D(2000)El Escorial revisited:revised criteria for the diagnosis of amyotrophic lateral sclerosis.Amyotroph Lateral Scler Other Motor Neuron Disord 1:293-299.
Chen G,Yue A,Ruan Z,Yin Y,Wang R,Ren Y,Zhu L(2014)Monitoring the biology stability of human umbilical cord-derived mesenchymal stem cells during long-term culture in serum-free medium.Cell Tissue Bank 15:513-521.
Chio A,Logroscino G,Traynor BJ,Collins J,Simeone JC,Goldstein LA,White LA(2013)Global epidemiology of amyotrophic lateral sclerosis:a systematic review of the published literature.Neuroepidemiology 41:118-130.
Cui F,Cai W,Wang Z,Ren Y,Li M,Sun Z,Huang X(2013)New mutation in the SOD1(copper/zinc superoxide dismutase-1)gene in a Chinese amyotrophic lateral sclerosis(ALS)patient.Amyotroph Lateral Scler Frontotemporal Degener 14:635-637.
Czarzasta J,Habich A,Siwek T,Czaplinski A,Maksymowicz W,Wojtkiewicz J(2017)Stem cells for ALS:An overview of possible therapeutic approaches.Int J Dev Neurosci 57:46-55.
Fecto F,Yan J,Vemula SP,Liu E,Yang Y,Chen W,Zheng JG,Shi Y,Siddique N,Arrat H,Donkervoort S,Ajroud-Driss S,Sufit RL,Heller SL,Deng HX,Siddique T(2011)SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.Arch Neurol 68:1440-1446.
Forostyak S,Sykova E(2017)Neuroprotective potential of cell-based therapies in ALS:from bench to bedside.Front Neurosci 11:591.
Frausin S,Viventi S,Verga Falzacappa L,Quattromani MJ,Leanza G,Tommasini A,Valencic E(2015)Wharton’s jelly derived mesenchymal stromal cells:Biological properties,induction of neuronal phenotype and current applications in neurodegeneration research.Acta Histochem 117:329-338.
Ge W,Ren C,Duan X,Geng D,Zhang C,Liu X,Chen H,Wan M,Geng R(2015)Differentiation of mesenchymal stem cells into neural stem cells using cerebrospinal fluid.Cell Biochem Biophys71:449-455.
Gordon PH(2011)Amyotrophic lateral sclerosis:pathophysiology,diagnosis and management.CNS Drugs 25:1-15.
Goutman SA(2017)Diagnosis and Clinical management of amyotrophic lateral sclerosis and other motor neuron disorders.Continuum(Minneap Minn)23:1332-1359.
Hass R,Kasper C,Bohm S,Jacobs R(2011)Different populations and sources of human mesenchymal stem cells(MSC):A comparison of adult and neonatal tissue-derived MSC.Cell Commun Signal 9:12.
Henkel JS,Beers DR,Zhao W,Appel SH(2009)Microglia in ALS:the good,the bad,and the resting.J Neuroimmune Pharmacol 4:389-398.
Jablecki CK,Berry C,Leach J(1989)Survival prediction in amyotrophic lateral sclerosis.Muscle Nerve 12:833-841.
Jaiswal MK(2018)Riluzole and edaravone:A tale of two amyotrophic lateral sclerosis drugs.Med Res Rev.
Kalaszczynska I,Ferdyn K(2015)Wharton’s jelly derived mesenchymal stem cells:future of regenerative medicine?Recent findings and clinical significance.Biomed Res Int 2015:430847.
Kano O,Iwamoto K,Ito H,Kawase Y,Cridebring D,Ikeda K,Iwasaki Y(2013)Limb-onset amyotrophic lateral sclerosis patients visiting orthopedist show a longer time-to-diagnosis since symptom onset.BMC Neurol 13:19.
Kikuchi K,Takeshige N,Miura N,Morimoto Y,Ito T,Tancharoen S,Miyata K,Kikuchi C,Iida N,Uchikado H,Miyagi N,Shiomi N,Kuramoto T,Maruyama I,Morioka M,Kawahara KI(2012)Beyond free radical scavenging:Beneficial effects of edaravone(Radicut)in various diseases(Review).Exp Ther Med 3:3-8.
Kwon MS,Noh MY,Oh KW,Cho KA,Kang BY,Kim KS,Kim YS,Kim SH(2014)The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALSpatients.J Neurochem 131:206-218.
Lewis KE,Rasmussen AL,Bennett W,King A,West AK,Chung RS,Chuah MI(2014)Microglia and motor neurons during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis:changes in arginase1 and inducible nitric oxide synthase.JNeuroinflammation 11:55.
Logroscino G,Traynor BJ,Hardiman O,Chio A,Couratier P,Mitchell JD,Swingler RJ,Beghi E,Eurals(2008)Descriptive epidemiology of amyotrophic lateral sclerosis:new evidence and unsolved issues.J Neurol Neurosurg Psychiatry 79:6-11.
Marconi S,Bonaconsa M,Scambi I,Squintani GM,Rui W,Turano E,Ungaro D,D’Agostino S,Barbieri F,Angiari S,Farinazzo A,Constantin G,Del Carro U,Bonetti B,Mariotti R(2013)Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model.Neuroscience 248:333-343.
Mazzini L,Fagioli F,Boccaletti R,Mareschi K,Oliveri G,Olivieri C,Pastore I,Marasso R,Madon E(2003)Stem cell therapy in amyotrophic lateral sclerosis:a methodological approach in humans.Amyotroph Lateral Scler Other Motor Neuron Disord 4:158-161.
Mazzini L,Mareschi K,Ferrero I,Vassallo E,Oliveri G,Boccaletti R,Testa L,Livigni S,Fagioli F(2006)Autologous mesenchymal stem cells:clinical applications in amyotrophic lateral sclerosis.Neurol Res 28:523-526.
Mazzini L,Mareschi K,Ferrero I,Miglioretti M,Stecco A,Servo S,Carriero A,Monaco F,Fagioli F(2012)Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis:a long-term safety study.Cytotherapy 14:56-60.
Mazzini L,Ferrero I,Luparello V,Rustichelli D,Gunetti M,Mareschi K,Testa L,Stecco A,Tarletti R,Miglioretti M,Fava E,Nasuelli N,Cisari C,Massara M,Vercelli R,Oggioni GD,Carriero A,Cantello R,Monaco F,Fagioli F(2010)Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis:a phase I clinical trial.Exp Neurol223:229-237.
Miller RG,Mitchell JD,Lyon M,Moore DH(2007)Riluzole for amyotrophic lateral sclerosis(ALS)/motor neuron disease(MND).Cochrane Database Syst Rev:CD001447.
Mora JS(2017)Edaravone for treatment of early-stage ALS.Lancet Neurol 16:772.
Morgan S,Orrell RW(2016)Pathogenesis of amyotrophic lateral sclerosis.Br Med Bull 119:87-98.
Moujalled D,White AR(2016)Advances in the development of disease-modifying treatments for amyotrophic lateral sclerosis.CNSDrugs 30:227-243.
Oh KW,Moon C,Kim HY,Oh SI,Park J,Lee JH,Chang IY,Kim KS,Kim SH(2015)Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis.Stem Cells Transl Med 4:590-597.
Petrou P,Gothelf Y,Argov Z,Gotkine M,Levy YS,Kassis I,Vaknin-Dembinsky A,Ben-Hur T,Offen D,Abramsky O,Melamed E,Karussis D(2016)Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis:results of phase 1/2 and 2a clinical trials.JAMA Neurol 73:337-344.
Petrov D,Mansfield C,Moussy A,Hermine O(2017)ALS clinical trials review:20 years of failure.Are we any closer to registering a new treatment?Front Aging Neurosci 9:68.
Prabhakar S,Marwaha N,Lal V,Sharma RR,Rajan R,Khandelwal N(2012)Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis:a pilot study.Neurol India 60:465-469.
Renton AE,Chio A,Traynor BJ(2014)State of play in amyotrophic lateral sclerosis genetics.Nat Neurosci 17:17-23.
Rosen DR,Siddique T,Patterson D,Figlewicz DA,Sapp P,Hentati A,Donaldson D,Goto J,O’Regan JP,Deng HX,et al.(1993)Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature 362:59-62.
Rosenbohm A,Liu M,Nagel G,Peter RS,Cui B,Li X,Kassubek J,Rothenbacher D,Lule D,Cui L,Ludolph AC,Group ALSRSS(2018)Phenotypic differences of amyotrophic lateral sclerosis(ALS)in China and Germany.J Neurol 265:774-782.
Rothstein JD(2017)Edaravone:A new drug approved for ALS.Cell171:725.
Rowland LP,Shneider NA(2001)Amyotrophic lateral sclerosis.NEngl J Med 344:1688-1700.
Rushkevich YN,Kosmacheva SM,Zabrodets GV,Ignatenko SI,Goncharova NV,Severin IN,Likhachev SA,Potapnev MP(2015)The use of autologous mesenchymal stem cells for cell therapy of patients with amyotrophic lateral sclerosis in belarus.Bull Exp Biol Med 159:576-581.
Sharma AK,Sane HM,Paranjape AA,Gokulchandran N,Nagrajan A,D’sa M,Badhe PB(2015)The effect of autologous bone marrow mononuclear cell transplantation on the survival duration in Amyotrophic Lateral Sclerosis-a retrospective controlled study.Am JStem Cells 4:50-65.
Siddique T,Figlewicz DA,Pericak-Vance MA,Haines JL,Rouleau G,Jeffers AJ,Sapp P,Hung WY,Bebout J,McKenna-Yasek D,et al.(1991)Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity.N Engl J Med 324:1381-1384.
Stifani N(2014)Motor neurons and the generation of spinal motor neuron diversity.Front Cell Neurosci 8:293.
Struys T,Moreels M,Martens W,Donders R,Wolfs E,Lambrichts I(2011)Ultrastructural and immunocytochemical analysis of multilineage differentiated human dental pulp-and umbilical cord-derived mesenchymal stem cells.Cells Tissues Organs 193:366-378.
Sun H,Sun C,Xiao W(2014)Expression regulation of co-inhibitory molecules on human natural killer cells in response to cytokine stimulations.Cytokine 65:33-41.
Tada S,Okuno T,Yasui T,Nakatsuji Y,Sugimoto T,Kikutani H,Sakoda S(2011)Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis.J Neuroinflammation 8:19.
Tang Y,Le W(2016)Differential roles of M1 and m2 Microglia in neurodegenerative diseases.Mol Neurobiol 53:1181-1194.
Thonhoff JR,Beers DR,Zhao W,Pleitez M,Simpson EP,Berry JD,Cudkowicz ME,Appel SH(2018)Expanded autologous regulatory T-lymphocyte infusions in ALS:A phase I,first-in-human study.Neurol Neuroimmunol Neuroinflamm 5:e465.
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