Remyelinating Drugs at a Crossroad: How to Improve Clinical Efficacy and Drug Screenings.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Remyelination*/drug effects ; Drug Evaluation, Preclinical*; Humans ; Animals ; Demyelinating Diseases/drug therapy ; Demyelinating Diseases/pathology ; Myelin Sheath/metabolism ; Oligodendroglia/drug effects ; Oligodendroglia/metabolism ; Oligodendroglia/cytology ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Neural Stem Cells/cytology ; Cell Differentiation/drug effects

Axons wrapped around the myelin sheath enable fast transmission of neuronal signals in the Central Nervous System (CNS). Unfortunately, myelin can be damaged by injury, viral infection, and inflammatory and neurodegenerative diseases. Remyelination is a spontaneous process that can restore nerve conductivity and thus movement and cognition after a demyelination event. Cumulative evidence indicates that remyelination can be pharmacologically stimulated, either by targeting natural inhibitors of Oligodendrocyte Precursor Cells (OPCs) differentiation or by reactivating quiescent Neural Stem Cells (qNSCs) proliferation and differentiation in myelinating Oligodendrocytes (OLs). Although promising results were obtained in animal models for demyelination diseases, none of the compounds identified have passed all the clinical stages. The significant number of patients who could benefit from remyelination therapies reinforces the urgent need to reassess drug selection approaches and develop strategies that effectively promote remyelination. Integrating Artificial Intelligence (AI)-driven technologies with patient-derived cell-based assays and organoid models is expected to lead to novel strategies and drug screening pipelines to achieve this goal. In this review, we explore the current literature on these technologies and their potential to enhance the identification of more effective drugs for clinical use in CNS remyelination therapies.

Nat Methods. 2012 Sep;9(9):917-22. (PMID: 22796663)
Comput Biol Med. 2022 Sep;148:105853. (PMID: 35870318)
Front Cell Dev Biol. 2021 Mar 08;9:653101. (PMID: 33763430)
Nat Chem Biol. 2022 Sep;18(9):925-933. (PMID: 35995862)
Nat Biotechnol. 2009 Mar;27(3):275-80. (PMID: 19252484)
Nat Protoc. 2019 Nov;14(11):3082-3100. (PMID: 31554955)
Cells. 2024 Apr 13;13(8):. (PMID: 38667289)
Acta Neuropathol. 2017 Sep;134(3):403-422. (PMID: 28631093)
J Neurosci. 2019 Mar 20;39(12):2184-2194. (PMID: 30696729)
Cell Chem Biol. 2019 Apr 18;26(4):593-599.e4. (PMID: 30773481)
ACS Pharmacol Transl Sci. 2019 Nov 14;2(6):372-386. (PMID: 32259071)
ACS Chem Neurosci. 2021 Jun 2;12(11):1835-1853. (PMID: 34008957)
N Engl J Med. 2012 Sep 20;367(12):1098-107. (PMID: 22992073)
EBioMedicine. 2021 Mar;65:103276. (PMID: 33714029)
Mult Scler. 2022 Jan;28(1):29-48. (PMID: 33870797)
Stem Cell Res. 2013 Jul;11(1):516-28. (PMID: 23562833)
Nat Commun. 2014 Jul 10;5:4355. (PMID: 25008467)
Acta Neuropathol Commun. 2018 Nov 19;6(1):124. (PMID: 30454040)
Stem Cell Reports. 2014 Aug 12;3(2):250-9. (PMID: 25254339)
J Med Chem. 2014 Jun 26;57(12):5074-84. (PMID: 24809814)
Annu Int Conf IEEE Eng Med Biol Soc. 2019 Jul;2019:2087-2090. (PMID: 31946312)
Nat Rev Immunol. 2015 Sep 15;15(9):545-58. (PMID: 26250739)
Cell. 2006 Aug 25;126(4):663-76. (PMID: 16904174)
Nat Rev Mol Cell Biol. 2023 May;24(5):334-354. (PMID: 36922629)
Cell Stem Cell. 2016 Nov 3;19(5):573-586. (PMID: 27814479)
Nature. 2016 Jul 28;535(7613):517-522. (PMID: 27437577)
Front Cell Neurosci. 2022 Jan 04;15:794675. (PMID: 35058753)
J Neurosci. 2016 Jul 27;36(30):7925-35. (PMID: 27466337)
Cell. 2014 Nov 6;159(4):766-74. (PMID: 25417154)
BMC Neurol. 2020 May 18;20(1):193. (PMID: 32423386)
Stem Cell Reports. 2014 Aug 12;3(2):312-23. (PMID: 25254344)
Cancer Cell. 2010 Apr 13;17(4):388-99. (PMID: 20385363)
Front Rehabil Sci. 2021 Dec 10;2:726436. (PMID: 36188781)
Biomed Eng Online. 2022 Mar 30;21(1):21. (PMID: 35354470)
Nat Commun. 2013;4:2965. (PMID: 24351982)
Int J Mol Sci. 2018 Nov 20;19(11):. (PMID: 30463396)
Stem Cell Reports. 2014 Apr 24;2(5):648-61. (PMID: 24936452)
Stem Cell Reports. 2019 May 14;12(5):890-905. (PMID: 31091434)
Neurochem Res. 2010 Dec;35(12):1978-2000. (PMID: 21127972)
Lancet. 2017 Dec 2;390(10111):2481-2489. (PMID: 29029896)
Lancet Neurol. 2018 Feb;17(2):162-173. (PMID: 29275977)
Biol Open. 2015 Jul 03;4(8):980-92. (PMID: 26142314)
Sci Rep. 2016 Jun 13;6:27690. (PMID: 27291783)
Nat Commun. 2021 Jan 28;12(1):652. (PMID: 33510160)
Science. 2016 Jan 22;351(6271):379-84. (PMID: 26798014)
Nature. 2015 Jun 11;522(7555):216-20. (PMID: 25896324)
J Mark Access Health Policy. 2017 Apr 10;5(1):1299833. (PMID: 28473889)
Elife. 2020 May 27;9:. (PMID: 32459173)
Acta Neuropathol. 2022 Feb;143(2):143-157. (PMID: 34860266)
J Neurosci. 2013 Jan 30;33(5):1759-72. (PMID: 23365216)
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13211-6. (PMID: 12235363)
Comput Methods Programs Biomed. 2022 Jun;221:106900. (PMID: 35623208)
Nat Commun. 2019 Nov 29;10(1):5446. (PMID: 31784517)
Semin Cell Dev Biol. 2021 Aug;116:3-9. (PMID: 33082115)
Life Sci. 2019 Jan 15;217:222-228. (PMID: 30543826)
Stem Cell Res Ther. 2019 Aug 27;10(1):272. (PMID: 31455382)
J Neurosci. 2006 Jul 26;26(30):7907-18. (PMID: 16870736)
Br J Dermatol. 1974 Feb;90(2):197-203. (PMID: 4594577)
Brain Res. 2016 May 1;1638(Pt B):209-220. (PMID: 26546966)
Cell Stem Cell. 2013 Feb 7;12(2):252-64. (PMID: 23395447)
Acta Neuropathol. 2020 Nov;140(5):715-736. (PMID: 32894330)
Elife. 2014 May 07;3:e02669. (PMID: 24843006)
Nat Neurosci. 2020 Jul;23(7):819-831. (PMID: 32424285)
BMC Med Educ. 2023 Sep 22;23(1):689. (PMID: 37740191)
Nature. 2019 Feb;566(7745):543-547. (PMID: 30747918)
Nature. 2019 Feb;566(7745):538-542. (PMID: 30675058)
FEBS Lett. 2018 Apr;592(7):1063-1078. (PMID: 29427507)
Sci Rep. 2018 Jan 11;8(1):478. (PMID: 29323240)
Nat Med. 2014 Aug;20(8):954-960. (PMID: 24997607)
Cell Stem Cell. 2016 May 5;18(5):573-86. (PMID: 27152442)
Life (Basel). 2021 Apr 09;11(4):. (PMID: 33918664)
Neuroimage Clin. 2021;30:102652. (PMID: 33872992)
Neurosci Bull. 2023 Mar;39(3):466-478. (PMID: 36853544)
Healthc Manage Forum. 2020 Jan;33(1):10-18. (PMID: 31550922)
Nat Rev Neurosci. 2008 Nov;9(11):839-55. (PMID: 18931697)
Neuroglia. 2018 Sep;1(1):91-105. (PMID: 30662979)
Nat Neurosci. 2021 Mar;24(3):437-448. (PMID: 33542524)
Biol Open. 2023 Mar 15;12(3):. (PMID: 36744877)
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4694-9. (PMID: 17360586)
Acta Neuropathol. 2014 Aug;128(2):191-213. (PMID: 24952885)
Nat Rev Neurosci. 2015 May;16(5):249-63. (PMID: 25891508)
Cureus. 2023 Sep 17;15(9):e45412. (PMID: 37854769)
STAR Protoc. 2021 Apr 07;2(2):100443. (PMID: 33851141)
J Neurovirol. 2022 Feb;28(1):17-26. (PMID: 35239145)
Glia. 2024 Aug;72(8):1469-1483. (PMID: 38771121)
J Neurosci. 2014 Oct 15;34(42):14128-46. (PMID: 25319708)
Cell Rep Med. 2020 Jul 21;1(4):100053. (PMID: 33205062)
Mol Autism. 2021 Feb 8;12(1):10. (PMID: 33557935)
Elife. 2016 Oct 05;5:. (PMID: 27705744)
J Neurosci. 2013 Jun 12;33(24):10143-53. (PMID: 23761909)
Front Aging Neurosci. 2020 Aug 06;12:247. (PMID: 32848716)
Nature. 2015 Oct 15;526(7573):448-52. (PMID: 26416758)
Mol Pharmacol. 2013 May;83(5):1020-9. (PMID: 23448715)
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Dec;1866(12):159041. (PMID: 34450268)
Front Cell Neurosci. 2023 Jan 26;17:1114781. (PMID: 36779010)
Dev Cell. 2021 May 3;56(9):1346-1358.e6. (PMID: 33945785)
J Neurosci Res. 2010 Sep;88(12):2546-57. (PMID: 20544820)
BMC Res Notes. 2016 Sep 05;9(1):419. (PMID: 27592856)
Lancet Neurol. 2020 Aug;19(8):678-688. (PMID: 32702337)
Cell Stem Cell. 2010 Jun 4;6(6):578-90. (PMID: 20569695)
Nature. 2018 Aug;560(7718):372-376. (PMID: 30046109)
Eur J Neurosci. 1999 Dec;11(12):4357-66. (PMID: 10594662)
Nat Rev Neurosci. 2017 Nov 16;18(12):753-769. (PMID: 29142295)
Development. 2004 Sep;131(17):4131-42. (PMID: 15280210)
J Neuroimmunol. 2018 Jul 15;320:1-10. (PMID: 29759134)
Ann Neurol. 1995 Nov;38(5):788-96. (PMID: 7486871)
Curr Biol. 2015 Sep 21;25(18):2411-6. (PMID: 26320951)
J Pers Med. 2021 Dec 11;11(12):. (PMID: 34945821)
Nat Rev Neurol. 2016 Sep;12(9):539-51. (PMID: 27514287)
Stem Cells Transl Med. 2020 Dec;9(12):1643-1650. (PMID: 32716131)
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9323-8. (PMID: 20439738)
Mult Scler Relat Disord. 2022 Jul;63:103839. (PMID: 35523059)
Cells. 2022 Apr 26;11(9):. (PMID: 35563770)
Science. 2010 Nov 5;330(6005):779-82. (PMID: 21051629)
Cells. 2022 Jul 21;11(14):. (PMID: 35883703)
Mult Scler Relat Disord. 2022 Mar;59:103673. (PMID: 35180619)
IEEE Trans Biomed Eng. 2021 Sep;68(9):2666-2677. (PMID: 33378257)
Nature. 2013 Oct 17;502(7471):327-332. (PMID: 24107995)
Nat Protoc. 2015 Aug;10(8):1143-54. (PMID: 26134954)
Exp Neurol. 2017 Feb;288:114-121. (PMID: 27865736)
Development. 2015 Dec 1;142(23):3983-95. (PMID: 26628089)
Mult Scler Relat Disord. 2023 May;73:104622. (PMID: 36958175)
Nat Rev Neurol. 2023 May;19(5):305-320. (PMID: 37059811)
Neuron. 2022 Nov 2;110(21):3549-3565. (PMID: 36228613)
Brain. 2008 Jun;131(Pt 6):1464-77. (PMID: 18490361)
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14071-6. (PMID: 12391318)
Cell. 2007 Nov 30;131(5):861-72. (PMID: 18035408)
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11807-E11816. (PMID: 30487224)
Int J Mol Sci. 2021 Mar 12;22(6):. (PMID: 33809224)
Nature. 2022 Mar;603(7899):152-158. (PMID: 35173329)
Cells. 2019 Aug 06;8(8):. (PMID: 31390799)
Front Cell Neurosci. 2021 Mar 17;15:631548. (PMID: 33815061)
J Neurol. 2017 Feb;264(2):304-315. (PMID: 27888416)
PLoS One. 2015 Dec 10;10(12):e0144550. (PMID: 26658258)
Trends Neurosci. 2016 Apr;39(4):246-263. (PMID: 26964504)
Nat Neurosci. 2022 Apr;25(4):415-420. (PMID: 35165460)
Semin Cell Dev Biol. 2019 Nov;95:42-53. (PMID: 30639325)
STAR Protoc. 2023 Dec 15;4(4):102725. (PMID: 37976154)
Front Cell Dev Biol. 2021 Jul 21;9:714169. (PMID: 34368163)
Mol Psychiatry. 2020 Feb;25(2):368-378. (PMID: 31455859)
Front Cell Neurosci. 2022 Jan 10;15:801704. (PMID: 35082605)
Pharmaceutics. 2019 Sep 02;11(9):. (PMID: 31480671)
Neuron. 2014 May 7;82(3):545-59. (PMID: 24811379)
ACS Chem Biol. 2022 Aug 19;17(8):2188-2200. (PMID: 35833657)
Acta Pharmacol Sin. 2019 Nov;40(11):1386-1393. (PMID: 30918344)
Mol Cell Neurosci. 2007 Mar;34(3):310-23. (PMID: 17196394)
J Neurol. 2021 Jan;268(1):30-44. (PMID: 31190170)
Science. 2021 Jun 11;372(6547):1205-1209. (PMID: 34112692)
Stem Cell Reports. 2020 Nov 10;15(5):1047-1055. (PMID: 33125874)
Annu Int Conf IEEE Eng Med Biol Soc. 2022 Jul;2022:1109-1112. (PMID: 36085783)
Molecules. 2020 Nov 12;25(22):. (PMID: 33198233)
Development. 2009 May;136(9):1443-52. (PMID: 19363151)
Stem Cell Reports. 2016 Jan 12;6(1):1-8. (PMID: 26724902)
Neuroscientist. 2015 Aug;21(4):356-71. (PMID: 24743306)
ACS Chem Biol. 2012 Jun 15;7(6):1040-8. (PMID: 22554036)
J Biol Chem. 2016 Feb 26;291(9):4356-73. (PMID: 26679998)
Sci Rep. 2020 Feb 11;10(1):1936. (PMID: 32041968)
Front Immunol. 2021 May 03;12:669811. (PMID: 34012452)
Mult Scler. 2022 Mar;28(3):331-345. (PMID: 35236198)

2023/R-Multi/001 Fondazione Italiana Sclerosi Multipla

Keywords: artificial Intelligence; central nervous system; drug discovery; iPSCs; multiple sclerosis; myelin; neurodegeneration; oligodendrocytes; organoids; remyelination

Date Created: 20240828 Date Completed: 20240828 Latest Revision: 20250124

20250124

PMC11352944

10.3390/cells13161326

39195216