Stem cell therapy in the treatment of Amyotrophic Lateral Sclerosis: systematic review
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Abstract
Introduction: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons, resulting in severe functional impairment. This study presents a systematic review of clinical trials published in the last decade regarding the use of stem cells in the treatment of ALS. Objective: To analyze the efficacy of cell transplantation, measured by the reduction of functional decline, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the secondary objective was to identify the type of stem cell and the route of administration that yielded the most promising outcomes to date. Methods: Articles were selected from the PubMed database using the descriptors "Amyotrophic Lateral Sclerosis," "stem cell therapies," and "motor neuron disease." Clinical studies conducted in humans and published between January 2013 and March 2024 were included. Results: The search identified 26 articles, of which 18 were selected and analyzed according to inclusion and exclusion criteria. Sequentially transplanted mesenchymal stem cells demonstrated the best results in reducing functional decline, particularly in patients at early stages of the disease. The repeated intrathecal route of administration was found to be the most promising for slowing disease progression, with fewer severe adverse effects. Conclusion: This study proposes that future research focus on the repeated transplantation of autologous mesenchymal cells via the intrathecal route.
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1. Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, et al. Amyotrophic lateral sclerosis. Lancet. 2022;400:10360):1363-80. https://doi.org/10.1016/S0140-6736(22)01272-7
2. Mejzini R, Flynn LL, Pitout IL, Fletcher S, Wilton SD, Akkari PA. ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now? Front Neurosci. 2019;13:1310. https://doi.org/10.3389/fnins.2019.01310
3. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942-55. https://doi.org/10.1016/S0140-6736(10)61156-7
4. Hardiman O, Al Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3(17071). https://doi.org/10.1038/nrdp.2017.71
5. Gonçalves JPN, Leoni TB, Martins MP, Peluzzo TM, Dourado Junior MET, Saute JAM, et al. Genetic epidemiology of familial ALS in Brazil. Neurobiol Anging. 2021;102(227):e1-e4. https://doi.org/10.1016/j.neurobiolanging.2021.01.007
6. Moura MC, Casulari LA, Novaes MRCG. Ethnic and demographic incidence of amyotrophic lateral sclerosis (ALS) in Brazil: A population-based study. Amyotrophic Lateral Scler Frontotemporal Degener. 2016;17(3-4):275-81. https://doi.org/10.3109/21678421.2016.1140210
7. Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, et al. Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol. 2022;21(5):480-93. https://doi.org/10.1016/s1474-4422(21)00465-8
8. Brooks BR, Miller RG, Swash M, Munsat TL. EL Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral https://doiAmyotrophic002/mus.27392r Other Motor Neuron Disord. 2000;1(5):293-9. https://doi.org/10.1080/146608200300079536
9. Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for the diagnosis of ALS. Clin Neurophysiol. 2008;119(3):497-503. https://doi.org/10.1016/j.clinph.2007.09.143
10. Vucic S, Ferguson TA, Cummings C, Hotchkin MT, Genge A, Glanzman R, et al. Gold Coast diagnostic criteria: Implications for ALS diagnosis and clinical trial enrollment. Muscle Nerve. 2021;64(5):532-7. https://doi.org/10.1002/mus.27392
11. Jauregui C, Blanco-Luquin I, Macías M, Roldan M, Caballero C, Pagola I, et al. Exploring the disease-associated microglia state in Amyotrophic Lateral Sclerosis. Biomedicines. 2023;11(11):2994. https://doi.org/10.3390/biomedicines11112994
12. Anderson G. Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides. Int J Mol Sci. 2022;24(1):587. https://doi.org/10.3390/ijms24010587
13. Wen X, Lan T, Su W, Cao B, Wang Y, ChenY. Latest progress and challenges in drug development for degenerative motor neuron diseases. Neural Regen Res. 2025. https://doi.org/10.4103/NRR.NRR-D-24-01266
14. Brasil: Ministério da Saúde. Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde. Departamento de Gestão e Incorporação de Tecnologias e Inovação em Saúde. Protocolo Clínico e Diretrizes Terapêuticas da Esclerose Lateral Amiotrófica. Brasília: Ministério da Saúde, 2021.
15. Kim SU, Vellis J. Steam cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009;87(10):2183-200. https://doi.org/10.1002/jnr.22054
16. Aljabri A, Halawani A, Lajdam GB, Labban S, Alshehri S, Felemban R. The safety and efficacy of stem cells therapy as an emerging therapy for ALS: a systematic review of controlled clinical trials. Front Neurol. 2021;12:783122. https://doi.org/10.3389/fneur.2021.783122
17. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169(1-2):13-21. https://doi.org/10.1016/S0022-510X(99)00210-5
18. Barker TH, Habibi N, Aromataris E, Stone JC, Leonardi-Bee J, Sears K, et al. The revised JBI critical appraisal tool for the assessment of risk of bias in quasi-experimental studies. JBI Evid Synth. 2024;22(3):378-88. https://doi.org/10.11124/JBIES-23-00268
19. Barker TH, Stone JC, Sears K, Klugar M, Tufanaru C, Leonardi-Bee J, et al. The revised JBI critical appraisal tool for the assessment of risk of bias for randomized controlled trials. JBI Evid Synth. 2023;21(3):494-506.
https://doi.org/10.11124/JBIES-22-00430
20. Sterne JAC, Hernán MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomized studies of interventions. BMJ. 2016;355:i4919. https://doi.org/10.1136/bmj.i4919
21. Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ. 2019;366:l4898. https://doi.org/10.1136/bmj.l4898
22. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71
23. Kim HY, Kim H, Oh K, Oh S, Koh S, Baik W, et al. Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study. Stem Cells. 2014;32(10):2724-31. https://doi.org/10.1002/stem.1770
24. Oh K, Moon C, Kim HY, Oh S, Park J, Lee JH, et al. Phase I Trial of Repeated Intrathecal Autologous Bone Marrow-Derived Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis. Stem Cells Transl Med. 2015;4(6):590-7. https://doi.org/10.5966/sctm.2014-0212
25. Rushkevich YN, Kosmacheva SM, Zabrodets GV, Ignatenko SI, Goncharova NV, Severin IN, et al. The use of autologous mesenchymal stem cells for cell therapy of patients with amyotrophic lateral sclerosis in Belarus. Bull Exp Biol Med. 2015;159(4):576-81. https://doi.org/10.1007/s10517-015-3017-3
26. Syková E, Rychmach P, Drahorádová I, Konrádová Š, Růžičková K, Voříšek, I, et al. Transplantation of Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial. Cell Transplant. 2017;26(4):647-58. https://doi.org/10.3727/096368916X693716
27. Petrou P, Gothelf Y, Argov Z, Gotkine M, Levy YS, Kassis I, et al. 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. 2016;73(3):337-44. https://doi.org/10.1001/jamaneurol.2015.4321
28. Berry JD, Cudkowicz ME, Windebank AJ, Staff NP, Owegi M, Nicholson K, et al. NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results. Neurology. 2019;93(24):e2294-305. https://doi.org/10.1212/WNL.0000000000008620
29. Siwek T, Jezierska-Wozniak K, Maksymowicz S, Barczewska M, Sowa M, Badowska W, et al. Repeat administration of bone marrow-derived mesenchymal stem cells for treatment of amyotrophic lateral sclerosis. Med Sci Monit. 2020;26:e927484. https://doi.org/10.12659/MSM.927484
30. Petrou P, Kassis I, Yaghmour NE, Ginzberg A, Karussis D. A phase II clinical trial with repeated intrathecal injections of autologous mesenchymal stem cells in patients with amyotrophic lateral sclerosis. Front Biosci (Landmark Ed). 2021;26(10):693-706. https://doi.org/10.52586/4980
31. Cudkowicz ME, Lindborg SR, Goyal NA, Miller RG, Burford MJ, Berry JD, et al. A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle Nerve. 2022;65(3):291-302. https://doi.org/10.1002/mus.27472
32. Barczewska M, Makymowicz S, Zdolinka-Malinowka I, Siwek T, Grudniak M. Umbilical cord mesenchymal stem cells in amyotrophic lateral sclerosis: an original study. Stem Cell Rev Rep. 2020;16(5):922-32. https://doi.org/10.1007/s12015-020-10016-7
33. Riley J, Glass J, Feldman EL, Polak M, Bordeau J, Federici T, et al. Intraspinal Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: a phase I trial, cervical microinjection, and final surgical safety outcomes. Neurosurgery. 2014;74(1):77-87. https://doi.org/10.1227/NEU.0000000000000156
34. Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Pensi MP, Muzi G, et al. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med. 2015;13:17. https://doi.org/10.1186/s12967-014-0371-2
35. Mazzini L, Gelati M, Profico DC, Sorarù G, Ferrari D, Copetti M, et al. Results from phase I clinical trial with intraspinal injection of neural stem cells in Amyotrophic Lateral Sclerosis: A long-term outcome. Stem Cells Transl Med. 2019;8(9):887-97. https://doi.org/10.1002/sctm.18-0154
36. Feldman EL, Boulis NM, Hur J, Johe K, Rutkove SB, Federici T, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Am Neurol. 2014;75(3):363-73. https://doi.org/10.1002/ana.24113
37. Glass JD, Hertzberg VS, Boulis NM, Riley J, Federici T, Polak M, et al. Transplantation of spinal cord–derived neural stem cells for ALS: Analysis of phase 1 and 2 trials. Neurology. 2016;87(4):392-400. https://doi.org/10.1212/WNL.0000000000002889
38. Baloh RH, Johnson JP, Avalos P, Allred P, Svendsen S, Gowing G, et al. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. Nat Med. 2022;28(9):1813-22. https://doi.org/10.1038/s41591-022-01956-3
39. Ruiz-Lopez FJ, Guardiola J, Izura V, Gómez-Espuch J, Iniesta F, Blanquer M, et al. Breathing pattern in a phase I clinical trial of intraspinal injection of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis. Respir Physiol Neurobiol. 2016;221:54-8. https://doi.org/10.1016/j.resp.2015.11.007
40. Yamashita T, Nakano Y, Sasaki R, Tadokoro K, Omote Y, Yunoki T, et al. Safety and Clinical Effects of a Muse Cell-Based Product in Patients with Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial. Cell Transpl. 2023;32:9636897231214370. https://doi.org/10.1177/09636897231214370