Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes paralysis whose etiology and pathogenesis have not been fully elucidated. Presently it is incurable and rapidly progressive with a survival of 2–5 years from onset, and no treatments could cure it. Therefore, it is urgent to identify which therapeutic target(s) are more promising to develop treatments that could effectively treat ALS. So far, more than 90 novel treatments for ALS patients have been registered on ClinicalTrials.gov, of which 23 are in clinical trials, 12 have been terminated and the rest suspended. This review will systematically summarize the possible targets of these novel treatments under development or failing based on published literature and information released by sponsors, so as to provide basis and support for subsequent drug research and development.
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Data Availability
All data generated or analyzed during this study were included in Table 1 and Supplementary Table 1.
Abbreviations
- ALS:
-
amyotrophic lateral sclerosis
- ROS:
-
radical/reactive oxygen species
- TDP-43:
-
TARDNA-binding protein of 43 kDa
- SOD1:
-
superoxide dismutase1
- FUS:
-
fused-in-sarcoma
- ERS:
-
endoplasmic reticulum stress
- UPR:
-
unfolded protein response
- fALS:
-
familiar ALS
- ASO:
-
antisense oligonucleotide
- ALSFRS-R:
-
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised
- Nfl:
-
neurofilament light chain
- OLE:
-
non-blind extended study
- ATXN2:
-
Ataxin-2
- FET:
-
FUS/EWSR1/TAF15
- Exportin 1:
-
XPO1
- eIF2B:
-
Eukaryotic translation initiation factor 2B
- HSPs:
-
heat shock proteins
- HSR:
-
heat shock response
- DLK:
-
dual leucine zipper kinase
- JNK:
-
c-Jun N-terminal kinases
- PERK:
-
protein kinase R-like endoplasmic reticulum kinase
- MPO:
-
myeloperoxidase
- GPX4:
-
Glutathione peroxidase 4
- TrkB:
-
tyrosine kinase receptor B
- CuII (atsm):
-
bis(thiosemicarbazone) copper (II)compound
- AuNPs:
-
gold nanoparticles
- D-PUFAs:
-
deuterated polyunsaturated fatty acids
- RIPK1:
-
receptor-interacting serine/threonine-protein kinase 1
- FDA:
-
the U.S. Food and Drug Administration
- EMA:
-
the European Medicines Agency
- MSCs:
-
Mesenchymal stem cells
- NTFs:
-
neurotrophic factors
- HGF:
-
Hepatocyte growth factor
- NIBS:
-
non-invasive brain stimulation
- rTMS:
-
repetitive transcranial magnetic stimulation
- tDCS:
-
transcranial direct current stimulation
- EAAT2:
-
excitatory amino acid transporter2
- FSTAs:
-
fast skeletal muscle troponin activators
- SVC:
-
slow vital capacity
- VEGF:
-
vascular endothelial growth factor
- NADH:
-
nicotinamide adenine dinucleotide hydride
- HSF1:
-
Heat Shock Factor 1
- NDA:
-
new drug applications
- GAPDH:
-
glyceraldehyde 3-phosphate dehydrogenase
- TCP:
-
Taylor-Couette-Poiseuille
- CSNs:
-
charge-stabilized nanostructures
- PI3K:
-
phosphatidylinositol-3-kinase
- Akt:
-
v-akt murine thymoma viral oncogene homologue
- Foxp3+:
-
forkhead box P3
- APC:
-
activated protein C
- iMNs:
-
induced motor neuron models
- DPR:
-
dipeptide-repeat protein
- ER:
-
endoplasmic reticulum
- Sigma-1 receptor:
-
Sigma non-opioid intracellular receptor 1
- MAM:
-
mitochondria-associated ER membrane
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This project was supported by the grants from National Natural Sciences Foundation of China (No. 82073835, and 81872855), CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-054), and Disciplines construction project (201920200802).
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Zhuo Sun performed the literature search, created the table and figures. Ying Peng and Bo Zhang contributed to the writing and editing of the manuscript. All authors read and approved this manuscript.
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Supplementary Table 1.
The overview of novel treatments for ALS that are terminated. The table summarizes the specific information of treatments terminated for lack of efficacy or safety
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Sun, Z., Zhang, B. & Peng, Y. Development of novel treatments for amyotrophic lateral sclerosis. Metab Brain Dis 39, 467–482 (2024). https://doi.org/10.1007/s11011-023-01334-z
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DOI: https://doi.org/10.1007/s11011-023-01334-z