Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy
Abstract
:1. Introduction
2. Neuropathology of MSA
3. Current Symptomatic Treatment of MSA
4. Potential Disease-Modifying Targets in MSA
4.1. Targeting alpha-Synuclein Aggregation
4.2. Targeting Neuroinflammation
4.3. Targeting Neuronal Loss
5. Limitations
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
3-NP | 3-nitropropionic acid |
AD | Alzheimer’s disease |
BDNF | brain-derived neurotrophic factor |
CGI-C | Clinical Global Impression of Change |
CNP | 2′-3′-cyclic nucleotide 3′-phosphodiesterase |
CNP-hα-syn mice | transgenic MSA mouse model overexpressing α-syn under a 2′-3′-cyclic nucleotide 3′-phosphodiesterase promoter |
CNS | central nervous system |
EAAT2 | excitatory amino acid transporter 2 |
EGCG | epigallocatechin gallate |
GCI | glial cytoplasmic inclusion |
GDH2 | glutamate dehydrogenase |
GDNF | glial cell line-derived neurotrophic factor |
hA53T α-syn | human A53T mutant form of α-syn |
IL | interleukins |
LRRK2 | leucine rich repeat kinase 2 |
MAO-B | monoaminooxidase B |
MBP | myelin basic protein |
MBP1-hα-syn mice | transgenic MSA mouse model expressing human α-syn under control of the myelin basic protein line 1 |
MPO | myeloperoxidase |
MS | multiple sclerosis |
MSA | multiple system atrophy |
MSA-C | cerebellar subtype of MSA |
MSA-P | parkinsonian subtype of MSA |
MSA-QoL | MSA-Quality of Life |
MSCs | mesenchymal stem cells |
mTOR | mechanistic target of rapamycin |
n.a. | not applicable |
NET | norepinephrine transporter |
NRF2 | nuclear-related factor 2 |
NRI | norepinephrine reuptake inhibitor |
NMDA | N-methyl-d- aspartic acid |
PD | Parkinson’s disease |
PDGFβ | platelet-derived growth factor β |
PLP-hα-syn mice | transgenic MSA mouse model overexpressing human α-syn under the proteolipid protein promoter |
PSP | progressive supranuclear palsy |
TNFα | tumor necrosis factor alpha |
TPPP/p25a | tubulin polymerization-promoting protein |
UMSARS | Unified Multiple System Atrophy Rating Scale |
VEGF | vascular endothelial growth factor |
α-syn | alpha-synuclein |
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Symptoms | Drug Therapy | Clinical Trials | ||
---|---|---|---|---|
Phase | NCT Number | Ref. | ||
Parkinsonism | MAO-B inhibitor safinamide | 2 | NCT03753763 | [50] |
Cerebellar ataxia | NMDA receptor modulator Tllsh2910 | 3 | NCT03901638 | [51] |
Orthostatic hypotension | α1-receptor inhibitor midodrine | 1 | NCT02897063 | [52] |
Norepinephrine prodrug droxidopa (l-threo DOPS) | 1 | NCT02897063 | [52] | |
4 | NCT02586623 | [53] | ||
Selective NET inhibitor atomexetine | 2 | NCT02796209 | [54] | |
NRI ampreloxetine (TD-9855) | 2 | NCT03750552 | [55] |
Therapeutic Targets | Drug Therapy | Clinical Trials | ||
---|---|---|---|---|
Phase | NCT Number | Ref. | ||
α-Synuclein aggregation | Vaccines Affitope PD01A and PD03A | 1 | NCT02270489 | [77] |
Epigallocatechin gallate (EGCG) | 3 | NCT02008721 | [78] | |
Chelator and antioxidant NMBI (Irminix) | 2 | NCT04184063 | [79] | |
Neuroinflammation | MPO inhibitor verdiperstat | 3 | NCT03952806 | [80] |
CD20-antibody rituximab | 2 | NCT04004819 | [81] | |
Neuronal loss | Bone marrow-derived mesenchymal stem cells (MSCs) | 1 | NCT03265444 | [82] |
1 | NCT02315027 | [83] | ||
n.a. | NCT02795052 | [84] | ||
1 | NCT04165486 | [85] | ||
Intranasal insulin | 2 | NCT02064166 | [86] | |
mTOR inhibitor sirolimus | 2 | NCT03589976 | [87] | |
Antioxidant inosine 5′-monophosphate | 2 | NCT03403309 | [88] |
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Mészáros, L.; Hoffmann, A.; Wihan, J.; Winkler, J. Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy. Int. J. Mol. Sci. 2020, 21, 2775. https://doi.org/10.3390/ijms21082775
Mészáros L, Hoffmann A, Wihan J, Winkler J. Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy. International Journal of Molecular Sciences. 2020; 21(8):2775. https://doi.org/10.3390/ijms21082775
Chicago/Turabian StyleMészáros, Lisa, Alana Hoffmann, Jeanette Wihan, and Jürgen Winkler. 2020. "Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy" International Journal of Molecular Sciences 21, no. 8: 2775. https://doi.org/10.3390/ijms21082775