Remyelinating Drugs at a Crossroad: How to Improve Clinical Efficacy and Drug Screenings
Abstract
:1. Introduction
2. The Biological Basis of Remyelination in Healthy and Multiple Sclerosis Pathological Conditions
2.1. Cells Participating in Remyelination
2.2. Signals Promoting Neural Precursor Cell Reactivation and Oligodendrocyte Precursor Cell Differentiation in the Adult Brain
2.3. Basis of Remyelination Failure in Multiple Sclerosis
2.4. Pharmacological Approaches for Remyelination
3. In Silico Models for Clinical Diagnosis and Drug Screenings
3.1. Artificial Intelligence-Driven Methods to Improve Multiple Sclerosis Diagnosis and Patient Stratification
3.2. Drug Repurposing through In Silico Binding
4. Disease-Relevant 2D and 3D Models for Drug Screenings and Physio-Pathological Studies
4.1. Generation of Oligodendrocyte Precursor Cells from Induced Pluripotent Stem Cells
4.2. Use of Induced Pluripotent Stem Cell-Derived Oligodendrocyte Precursor Cells to Study Demyelinating Diseases
4.3. Organoid-Derived Models for the Screening of Remyelinating Drugs
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADE | Acute Disseminated Encephalomyelitis | |
AI | Artificial Intelligence | |
aNSCs | activated Neural Stem Cells | |
BBB | Blood–Brain Barrier | |
Bcas1 | Brain-enriched myelin-associated protein 1 | |
bFGF | basic Fibroblast Growth Factor | |
BMPs | Bone Morphogenetic Proteins | |
c-Myc | Cellular myelocytomatosis oncogene | |
cAMP | cyclic AMP | |
CC | Corpus Callosum | |
CIS | Clinically Isolated Syndrome | |
CNNs | Convolutional Neural Networks | |
CNPase | 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase | |
CNS | Central Nervous System | |
CNTF | Ciliary Neurotrophic Factor | |
CRISPR | Clustered regularly interspaced palindromic repeats | |
CSF | Cerebrospinal Fluid | |
CTIP2 | COUP-TF-interacting protein 2 | |
CypD | Cyclophilin D | |
CYP51 | Sterol 14-demethylase | |
DG | Dentate Gyrus | |
DLX1 | Distal-Less Homeobox 1 | |
DMTs | Disease-Modifying Therapies | |
DSB | Dorsomorphin, SB431542, and BIO | |
DTs | Digital Twins | |
EAE | Experimental Autoimmune Encephalomyelitis | |
EBs | Embryoid Bodies | |
EBP | Emopamil Binding Protein | |
EGF | Epidermal Growth Factor | |
EMX1 | Empty Spiracles Homeobox 1 | |
Enpp8 | Ectonucleotide pyrophosphatase/phosphodiesterase 8 | |
ESCs | Embryonic Stem Cells | |
FDA | Food and Drug Administration | |
FGF | Fibroblast Growth Factor | |
GFP | Green Fluorescent Protein | |
Gli1-3 | Glioma-associated oncogene family zinc finger proteins | |
GPCRs | G protein-coupled receptors | |
GPR17 | G protein-coupled receptor 17 | |
GR | Glucocorticoid Receptor | |
Hh | Hedgehog | |
hiOLs | human iPSCs-derived oligodendrocytes | |
IGF1 | Insulin-like Growth Factor 1 | |
iPSCs | induced Pluripotent Stem Cells | |
JCV | John Cunningham Virus | |
Klf4 | Krüppel-Like Factor 4 | |
LDN | LDN-193189 | |
LGA | Lamarckian Genetic Algorithm | |
LHX6 | LIM Homeobox 6 | |
LINGO-1 | Leucine-rich and Immunoglobin-like domain-containing protein 1 | |
LTP | Long-Term Potentiation | |
MACS | Magnetic Activated Cell Sorting | |
MAG | Myelin-Associated Glycoprotein | |
Mal | Myelin and lymphocyte protein | |
MBP | Myelin Basic Protein | |
MD | Molecular Dynamics | |
ML | Machine Learning | |
MRI | Magnetic Resonance Imaging | |
MS | Multiple Sclerosis | |
MyRF | Myelin Regulatory Factor | |
NADH | Nicotinamide adenine dinucleotide reduced form | |
NECs | Neuro-Epithelial Cells | |
NG2 | Neural antigen 2 | |
NKX2.2 | NK2 Homeobox 2 | |
NMDA | N-methyl-D-aspartate | |
NMO | Neuro-Myelitis Optica | |
Notch | Neurogenic locus notch homolog protein | |
NPCs | Neural Precursor Cells | |
NSCs | Neural Stem Cells | |
OCT | Optical Coherence Tomography | |
Oct3/4 | Octamer-binding Transcription factor 3/4 | |
OLs | myelinating Oligodendrocytes | |
Opalin | Oligodendrocytic myelin paranodal and inner loop protein | |
OPCs | Oligodendrocyte Precursor Cells | |
PAX6 | Paired Box 6 | |
PBMCs | Peripheral Blood Mononuclear Cells | |
PDGF | Platelet-Derived Growth Factor | |
PDGFRα | Platelet-Derived Growth Factor Receptor alpha | |
PLLA | poly(L-lactic acid) | |
PLP1 | Proteolipid Protein 1 | |
PM | Purmorphamine | |
PMD | Pelizaeus-Merzbacher Disease | |
PML | Progressive Multifocal Leukoencephalitis | |
pOPCs | parenchymal Oligodendrocyte Precursor Cells | |
PPMS | Primary Progressive Multiple Sclerosis | |
PS | Polystyrene | |
Ptch | Patched | |
qNSCs | quiescent Neural Stem Cells | |
QSAR | Quantitative Structure–Activity Relationships | |
RA | Retinoic Acid | |
RMSD | Root–Mean–Square Deviation | |
RMSF | Root–Mean–Square Fluctuation | |
ROS | Reactive Oxygen Species | |
RRMS | Relapsing–Remitting Multiple Sclerosis | |
RT-qPCR | Reverse Transcription-quantitative Polymerase Chain Reaction | |
S14R | Sterol C-14 reductase | |
S1PL | Sphingosine 1-Phosphate receptor Lyase | |
SAG | Smoothened agonist | |
SDF-1 | Stromal cell–derived factor 1 | |
SGZ | Sub Granular Zone | |
Shh | Sonic Hedgehog | |
SMAD | Suppressor of Mothers Against Decapentaplegic | |
Smo | Smoothened | |
SOX1 | SRY-box 1 | |
Sox2 | SRY-box 2 | |
SOX10 | SRY-box 10 | |
SPMS | Secondary Progressive Multiple Sclerosis | |
SVZ | Subventricular Zone | |
T3 | triiodo-L-thyronine | |
TBR1 | T-box brain Transcription Factor 1 | |
TBR2 | T-box brain Transcription Factor 2 | |
TGF-β | Transforming Growth Factor-β | |
TRPA1 | Transient Receptor Potential Ankyrin 1 |
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Compound | Primary Targets | Targets of Interest |
---|---|---|
Bazedoxifene | Estrogen receptor [3,14] | EBP [3] |
Benztropine | Muscarinic receptor [15] | EBP [9] |
Clemastine | Histamine/muscarinic [3,16] | EBP [9] |
Clobetasol | Glucocorticoid Receptor (GR) [17,18] | Smo [12,19] |
Clotrimazole | Fungal CYP51 [20] | CYP51 [9,20], Smo [21] |
Donepezil | Acetylcholinesterase [3,22] | EBP [3] |
Fluphenazine | Antipsychotic; multiple receptors [3] | EBP [3] |
GSA-10 | Smo [11,23] | Smo [11,23] |
GSK239512 | Histamine H3 receptors [24] | EBP [3] |
Halcinonide | GR [19] | Smo [12] |
Hydroxyzine | Histamine receptors [3] | EBP [3] |
Ifenprodil | N-methyl-D-aspartate (NMDA) receptors [3,25] | S14R [3] |
Itraconazole | Fungal CYP51 [20] | CYP51 [20], Smo [21,26,27] |
Ketoconazole | Fungal CYP51 [3,21] | CYP51 [3], Smo [9,21,26,27] |
Medroxyprogesterone acetate | Progesterone receptor [3,14] | CYP51 [9] |
Megestrol | Progesterone receptor [3,14] | CYP51 [3] |
Miconazole | Fungal CYP51 [17] | CYP51 [9], Smo [21] |
Quetiapine | Atypical antipsychotic [3] | EBP [3] |
Raloxifene | Estrogen receptor [3,14] | EBP [3] |
Ro 25-6981 | NMDA receptors [3] | S14R [3] |
Salmeterol | Adrenergic receptors [3] | S14R [3] |
SANT-1 | Smo [10,27,28,29] | Smo [10,27,28,29] |
Tamoxifen | Estrogen receptor [3,14] | EBP [9] |
Toremifene | Estrogen receptor [3,14] | EBP [3] |
U50488 | k-opioid receptor [3] | EBP [3] |
Vanoxerine | Multiple ion channel families [3] | EBP [3] |
Vesamicol | Vesicular acetylcholine transport [3,30] | EBP [3] |
Compounds | Targets | ClinicalTrials.Gov ID | Trial Stage | Details [31] | Trial Status |
---|---|---|---|---|---|
Liothyronine | Thyroid hormone receptor alpha and beta [32] | NCT0276005 | 1 | Thyroid Hormone for Remyelination in Multiple Sclerosis (MS): A Safety and Dose Finding Study (MST3K). This is a phase 1 study evaluating the safety and maximum tolerated dose of Liothyronine (T3) in subjects with multiple sclerosis. | Completed (October 2017) |
BIIB061 | Tau [33] | NCT02521545 | 1 | Single-Dose Study of a New Formulation of BIIB061. The primary objective of the study is to assess the pharmacokinetic (PK) profile of BIIB061 in the new oral formulation in the fasted state in healthy male and female volunteers. | Completed (August 2015) |
BIIB033 (Opicinumab) | Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (LINGO-1) [34] | NCT01244139 | 1 | Safety Study of BIIB033 in Subjects with Multiple Sclerosis. The main purpose of the study is to evaluate the safety, tolerability, and pharmacokinetic profile of two intravenous infusions of BIIB033 administered two weeks apart in subjects with MS. | Completed (April 2012) |
Natalizumab | Integrin alpha-4 [32] | NCT00559702 | 1 | Safety Study of Natalizumab to Treat Multiple Sclerosis (MS). The primary objective of this study is to compare the pharmacokinetic and pharmacodynamics of single subcutaneous and intramuscular doses of 300 mg natalizumab to intravenous administration of 300 mg natalizumab in MS participants. | Completed (November 2011) |
Olesoxime | Mitochondrial permeability transition pore [32] | NCT01808885 | 1 | Safety Study of Olesoxime in Patients With Stable Relapsing–Remitting Multiple Sclerosis Treated With Interferon Beta. (MSREPAIR). This is a 24-week phase 1b, randomized, double-blind, placebo-controlled, parallel-group, multicentre safety study comparing the tolerance profile of olesoxime (495 mg, od) when administered on top of Interferon beta in patients with stable RRMS. | Completed (January 2014) |
Metformin | Electron transfer flavoprotein-ubiquinone oxidoreductase, 5′-AMP-activated protein kinase subunit beta-1 [32] | NCT05893225 | 2 | Metformin Add-on Clinical Study in Multiple Sclerosis to Evaluate Brain Remyelination and Neurodegeneration. This clinical trial aims to demonstrate that metformin can prevent clinical disability in patients with progressive MS by stopping or slowing down neurodegeneration by enhancing endogenous remyelination. | Recruiting |
Ifenprodil | Glutamate receptor ionotropic, N-methyl-D-aspartate (NMDA) 1 and 2B [32] | NCT06330077 | 2 | Ifenprodil as a ReMyelinating repurpOsed Drug in Multiple Sclerosis (MODIF-MS). The preclinical research has allowed for the identification of ifenprodil as a powerful drug to promote myelin repair in vitro and in vivo across species. | Not yet recruiting |
Metformin | Electron transfer flavoprotein-ubiquinone oxidoreductase, 5′-AMP-activated protein kinase subunit beta-1 [32] | NCT04121468 | 2 | A Phase I Double-Blind Study of Metformin Acting on Endogenous Neural Progenitor Cells in Children With Multiple Sclerosis. A randomized multiple baseline feasibility trial where participants will start taking metformin at one of 3 randomly determined points (3 months, 6 months or 9 months) during the 12-month trial. | Unknown |
Quetiapine | 5-hydroxytryptamine receptor 2A, D2 dopamine receptor [32] | NCT02087631 | 2 | Safety and Tolerability of Quetiapine in Multiple Sclerosis. The purpose of this clinical trial is to determine if extended-release quetiapine in a dose of 300 mg daily is tolerable to people with RRMS and progressive MS. | Completed (July 2019) |
Metformin; Clemastine | Electron transfer flavoprotein-ubiquinone oxidoreductase, 5′-AMP-activated protein kinase subunit beta-1; Histamine H1 receptor [32] | NCT05131828 | 2 | CCMR Two: A Phase IIa, Randomised, Double-blind, Placebo-controlled Trial of the Ability of the Combination of Metformin and Clemastine to Promote Remyelination in People With Relapsing–remitting Multiple Sclerosis Already on Disease-modifying Therapy. The goal is to establish whether the combination of metformin and clemastine can promote remyelination in people with MS. | Recruiting |
Adrenocorticotropin | Adrenocorticotropic hormone receptor [32] | NCT00986960 | 2 | Effect of Adrenocorticotropin Injection With Weekly Interferon Beta in Patients With Relapsing–Remitting Multiple Sclerosis (MS) (ACTH). The purpose of this study is to evaluate whether the use of ACTH in addition to Avonex is effective in the treatment of RRMS. | Withdrawn (December 2010) |
BIIB033 (Opicinumab) | LINGO-1 [34] | NCT03222973 | 2 | Efficacy and Safety of BIIB033 (Opicinumab) as an Add-on Therapy to Disease-Modifying Therapies (DMTs) in Relapsing Multiple Sclerosis (MS) (AFFINITY). The primary objective of Part 1 of this study is to evaluate the effects of BIIB033 versus placebo on disability improvement over 72 weeks. | Terminated (February 2021) |
Metformin | Electron transfer flavoprotein-ubiquinone oxidoreductase, 5′-AMP-activated protein kinase subunit beta-1 [32] | NCT05298670 | 2 | Drug Repurposing Using Metformin for Improving the Therapeutic Outcome in Multiple Sclerosis Patients. This study aims to evaluate the effect of Metformin as an add-on therapy for improving the outcome in RRMS patients. | Recruiting |
BIIB061; Interferon-beta1; Glatiramer acetate | Tau [33]; Interferon alpha/beta receptor 1 [32]; Major Histocompatibility Complex [35] | NCT04079088 | 2 | Study to Evaluate Oral BIIB061 Added to Interferon-beta1 (IFN-β1) or Glatiramer Acetate in Relapsing Multiple Sclerosis (RMS). The primary objectives of the study are to evaluate the safety of BIIB061 versus placebo in participants with RMS and to evaluate the efficacy of BIIB061 to improve disability outcome versus placebo in participants with RMS. | Withdrawn |
Bazedoxifene acetate | Estrogen receptor [32] | NCT04002934 | 2 | Bazedoxifene Acetate as a Remyelinating Agent in Multiple Sclerosis (ReWRAP). The primary goal of this study is to assess the efficacy of bazedoxifene (BZA) as a remyelinating agent in patients with RRMS. | Recruiting |
CNM-Au8 | Nicotinamide adenine dinucleotide reduced form (NADH) [36] | NCT03536559 | 2 | Nanocrystalline Gold to Treat Remyelination Failure in Chronic Optic Neuropathy In Multiple Sclerosis (VISIONARY-MS). The objective of this trial is to assess the efficacy and safety of CNM-Au8 as a remyelinating treatment for vision-impairing MS lesions in participants who have chronic vision impairment as a result of RRMS. | Terminated (July 2022) |
Domperidone | D2 and D3 dopamine receptors [32] | NCT02493049 | 2 | Pilot Trial of Domperidone in Relapsing–Remitting Multiple Sclerosis (RRMS). The first major objective of this pilot trial is to demonstrate that it is possible to study myelin repair in relapsing–remitting multiple sclerosis (RRMS) patients with enhancing lesions on MRI by using advanced imaging techniques. | Completed (February 2019) |
Testosterone | Androgen receptor [32] | NCT03910738 | 2 | TOTEM RRMS: TestOsterone TreatmEnt on Neuroprotection and Myelin Repair in Relapsing–Remitting Multiple Sclerosis (TOTEM-RRMS). The trial sought to demonstrate the effect of testosterone supplementation in testosterone-deficient patients in a multicentre, randomized, parallel-group, double-blind, placebo-controlled trial. The main objective will be to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging and thalamic atrophy analyses. | Recruiting |
Clemastine | Histamine H1 receptor [32] | NCT02040298 | 2 | Assessment of Clemastine Fumarate as a Remyelinating Agent in Multiple Sclerosis (ReBUILD). The main purpose of this study is to assess clemastine as a remyelinating agent in patients with relapsing forms of multiple sclerosis. | Completed (April 2016) |
Phenytoin | Sodium channel protein type 1, 2, 5 and 8 subunit alpha, Potassium voltage-gated channel subfamily H member 2, Voltage-dependent L-type calcium channel [32] | NCT01451593 | 2 | Neuroprotection With Phenytoin in Optic Neuritis. The purpose of this study is to determine whether phenytoin (which blocks sodium entry into cells) can protect against loss of nerve fibres and prevent loss of vision after optic neuritis. | Completed (March 2015) |
GSK239512 | Histamine H3 receptor [35] | NCT01772199 | 2 | Study to Assess Whether GSK239512 Can Remyelinate Lesions in Subjects with Relapsing–Remitting Multiple Sclerosis. This is a randomized, parallel-group, placebo-controlled study designed to assess whether GSK239512 can enhance lesion remyelination in subjects with RRMS. | Completed (September 2014) |
Natalizumab | Integrin alpha-4 [32] | NCT05418010 | 2 | Natalizumab for the Treatment of People With Inflammatory Demyelination Suggestive of Multiple Sclerosis, or Definite Multiple Sclerosis, at First Presentation (AttackMS) (AttackMS). Evidence suggests that shutting down inflammation using highly effective DMTs early after diagnosis leads to better long-term clinical outcomes. The AttackMS trial will test the effect of starting a highly effective DMT licensed for MS, Tysabri® (Natalizumab 300 mg), within a short time—14 days—after symptom onset. | Recruiting |
BGC20-0134 | / | NCT01037907 | 2 | A Study of Orally Administered BGC20-0134 (Structured Lipid) in Patients With Relapsing–Remitting Multiple Sclerosis (RRMS). To determine the efficacy and safety of an oral drug (BGC20-0134) in patients with RRMS. Specifically, the cumulative number of new gadolinium-enhancing lesions after 24 weeks of treatment with BGC20-0134. | Terminated (December 2011) |
EHP-101 | Peroxisome proliferator-activated receptor gamma, Cannabinoid receptor 2 [35] | NCT04909502 | 2 | Evaluation of Safety, Tolerability and Preliminary Efficacy of EHP-101 in Relapsing Forms of Multiple Sclerosis. The purpose of this trial is to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of EHP-101 in adult subjects with Relapsing Forms of Multiple Sclerosis. | Suspended (April 2024) |
Clemastine | Histamine H1 receptor [32] | NCT02521311 | 2 | Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER). The main purpose of this study is to assess Clemastine as a remyelinating agent in patients with acute optic neuritis. | Recruiting |
Vaginal Estriol | Estrogen receptor alpha [32] | NCT03774407 | 3 | Vaginal Estriol in Multiple Sclerosis. Study to evaluate the efficiency of vaginal estriol, as a treatment for urogenital symptoms in female patients with RRMS. | Completed (November 2020) |
Clemastine | Histamine H1 receptor [32] | NCT05338450 | 3 | Clemastine Fumarate as Remyelinating Treatment in Internuclear Ophthalmoparesis and Multiple Sclerosis (RESTORE). The (long-term) effects of clemastine need to be confirmed in clinical models for MS. Internuclear ophthalmoparesis (INO) may be used as a clinical model for investigating remyelinating therapies by measuring horizontal eye movements with infrared oculography. | Recruiting |
Nomegestrol acetate; Estradiol | Progesterone receptor [34]; Estrogen receptor alpha and beta [32] | NCT00127075 | 3 | POPART’MUS: Prevention of Post-Partum Relapses With Progestin and Estradiol in Multiple Sclerosis. The POPART’MUS study is a European, multicentre, randomized, placebo-controlled and double-blind clinical trial, which aims to prevent MS relapses related to the post-partum condition, by administering high doses of progestin (nomegestrol acetate), in combination with endometrial protective doses of estradiol. | Unknown |
CNM-Au8 | NADH [36] | NCT04626921 | 3 | A Multi-Center, Open-Label Long-Term Extension Study of CNM-Au8 in Patients With Stable Relapsing Multiple Sclerosis (VISIONMS-LTE). This open-label, long-term extension study is only available to participants who have completed CNMAu8.201 (VISIONARY-MS). The Week 48/End-of-Study Visit for study CNMAu8.201 (VISIONARY-MS) will serve to establish the Baseline for electrophysiological, functional, and morphological vision testing, as well as the neurological and outcome assessments. | Completed (September 2023) |
Cladribine | Ribonucleoside-diphosphate reductase large subunit, subunit M2 and M2 B, DNA polymerase alpha catalytic subunit, epsilon catalytic subunit A, epsilon subunit 2, 3 and 4, Purine nucleoside phosphorylase [32] | NCT05902429 | 4 | Effects of Oral Cladribine on Remyelination and Inflammation in Multiple Sclerosis Patients (CLAREMI). The present study is based on the hypothesis that improved inflammatory control through cladribine tablets provides a tissue microenvironment more favourable for remyelination of brain lesions in MS. | Active, not recruiting (January 2024) |
Alemtuzumab | CAMPATH-1 (CD52) antigen [32] | NCT01395316 | 4 | Alemtuzumab on Surrogate Markers of Disease Activity and Repair Using Advanced MRI Measures in Subjects with Relapsing–Remitting Multiple Sclerosis. The MRI study is designed to identify possible mechanisms by which alemtuzumab acts to protect the brain from inflammation and how it may enhance repair through remyelination. | Completed (July 2017) |
Rebif | Interferon alpha/beta receptors 1 and 2 [32] | NCT01085318 | 4 | Rebif Advanced Magnetic Resonance Imaging (MRI) and Immunology Pilot Trial. The purpose of this trial is to evaluate the effects of Rebif® 44 mcg subcutaneous (sc) three times a week (tiw) on (a) remyelination/demyelination, (b) lesion and brain volume, (c) central nervous system (CNS) iron deposition, and (d) immune status in subjects with RRMS via several MRI techniques. | Completed (March 2012) |
Adrenocorticotropin | Adrenocorticotropic hormone receptor [32] | NCT02446886 | 4 | Adrenocorticotropic Hormone (ACTH) Effects on Myelination in Subjects With MS. The primary objective of this study is to determine if monthly pulse doses of a three-day course of ACTH (H.P. Acthar®) are more effective at recovering myelin at 12 months, as measured by myelin water fraction (MWF), in new MS lesions as compared to one course of treatment. | Terminated (June 2020) |
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Al Jaf, A.I.A.; Peria, S.; Fabiano, T.; Ragnini-Wilson, A. Remyelinating Drugs at a Crossroad: How to Improve Clinical Efficacy and Drug Screenings. Cells 2024, 13, 1326. https://doi.org/10.3390/cells13161326
Al Jaf AIA, Peria S, Fabiano T, Ragnini-Wilson A. Remyelinating Drugs at a Crossroad: How to Improve Clinical Efficacy and Drug Screenings. Cells. 2024; 13(16):1326. https://doi.org/10.3390/cells13161326
Chicago/Turabian StyleAl Jaf, Aland Ibrahim Ahmed, Simone Peria, Tommaso Fabiano, and Antonella Ragnini-Wilson. 2024. "Remyelinating Drugs at a Crossroad: How to Improve Clinical Efficacy and Drug Screenings" Cells 13, no. 16: 1326. https://doi.org/10.3390/cells13161326