Novel Genome-Editing-Based Approaches to Treat Motor Neuron Diseases: Promises and Challenges

Scientists review genome editing approaches aimed either at correcting the disease-causing mutations or at modulating the expression of genetic modifiers, e.g. by repairing SOD1 mutations or SMN2 splicing defect, or deleting C9orf72 expanded repeats.
[Molecular Therapy]
Miccio, A., Antoniou, P., Ciura, S., & Kabashi, E. (2021). Novel genome-editing-based approaches to treat motor neuron diseases: promises and challenges. Molecular Therapy, 0(0). https://doi.org/10.1016/j.ymthe.2021.04.003 Cite
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Ionis Initiates Phase III Trial of Novel Antisense Medicine to Treat Leading Cause of Juvenile-Onset ALS

Ionis Pharmaceuticals, Inc. announced the initiation of a Phase III clinical trial of ION363 in patients with amyotrophic lateral sclerosis (ALS) with mutations in the fused in sarcoma gene.
[Ionis Pharmaceuticals, Inc.]
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Adipose Derived Stem Cells Protect Motor Neurons and Reduce Glial Activation in both In Vitro and In Vivo Models of ALS

Researchers tested the in vitro neuroprotective potential of mouse adipose derived stem cells in astrocyte/motor neuron co-cultures where amyotrophic lateral sclerosis (ALS) astrocytes show neurotoxicity.
[Molecular Therapy-Methods & Clinical Development]
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A RIPK1-Regulated Inflammatory Microglial State in Amyotrophic Lateral Sclerosis

The authors identified a subclass of microglia in mouse models of ALS which we term receptor-interacting protein kinase 1 (RIPK1)-Regulated Inflammatory Microglia.
[Proceedings of the National Academy of Sciences of the United States of America]
Mifflin, L., Hu, Z., Dufort, C., Hession, C. C., Walker, A. J., Niu, K., Zhu, H., Liu, N., Liu, J. S., Levin, J. Z., Stevens, B., Yuan, J., & Zou, C. (2021). A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences, 118(13). https://doi.org/10.1073/pnas.2025102118 Cite
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Modulation of the IGF1R-MTOR Pathway Attenuates Motor Neuron Toxicity of Human ALS SOD1G93A Astrocytes

The authors showed elevated activation of the MTOR pathway in human-derived astrocytes harboring mutant SOD1, which resulted in inhibition of macroautophagy/autophagy, increased cell proliferation, and enhanced astrocyte reactivity.
[Autophagy]
Granatiero, V., Sayles, N. M., Savino, A. M., Konrad, C., Kharas, M. G., Kawamata, H., & Manfredi, G. (2021). Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1G93A astrocytes. Autophagy, 0(0), 1–14. https://doi.org/10.1080/15548627.2021.1899682 Cite
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S-Nitrosylated TDP-43 Triggers Aggregation, Cell-to-Cell Spread, and Neurotoxicity in hiPSCs and In Vivo Models of ALS/FTD

The authors showed environmentally induced nitrosative stress triggered protein aggregation and cell-to-cell spread.
[Proceedings of the National Academy of Sciences of the United States of America]
Pirie, E., Oh, C., Zhang, X., Han, X., Cieplak, P., Scott, H. R., Deal, A. K., Ghatak, S., Martinez, F. J., Yeo, G. W., Yates, J. R., Nakamura, T., & Lipton, S. A. (2021). S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD. Proceedings of the National Academy of Sciences, 118(11). https://doi.org/10.1073/pnas.2021368118 Cite
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Kadimastem Granted a Patent in Israel for the Treatment of ALS

Kadimastem Ltd. announced that it has been granted a patent by The Israel Patent Office for its differentiated human astrocytes from human pluripotent stem cells for use in the treatment and drug screening of Amyotrophic Lateral Sclerosis (ALS).
[Kadimastem Ltd.]
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Current and Future Applications of Induced Pluripotent Stem Cell-Based Models to Study Pathological Proteins in Neurodegenerative Disorders

Scientists explore the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discuss advantages and limitations of this model, and present emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.
[Molecular Psychiatry]
de Rus Jacquet, A., Denis, H. L., Cicchetti, F., & Alpaugh, M. (2021). Current and future applications of induced pluripotent stem cell-based models to study pathological proteins in neurodegenerative disorders. Molecular Psychiatry, 1–22. https://doi.org/10.1038/s41380-020-00999-7 Cite
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p53 Is a Central Regulator Driving Neurodegeneration Caused by C9orf72 poly(PR)

Researchers developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration.
[Cell]
Maor-Nof, M., Shipony, Z., Lopez-Gonzalez, R., Nakayama, L., Zhang, Y.-J., Couthouis, J., Blum, J. A., Castruita, P. A., Linares, G. R., Ruan, K., Ramaswami, G., Simon, D. J., Nof, A., Santana, M., Han, K., Sinnott-Armstrong, N., Bassik, M. C., Geschwind, D. H., Tessier-Lavigne, M., … Gitler, A. D. (2021). p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell, 0(0). https://doi.org/10.1016/j.cell.2020.12.025 Cite
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MediciNova Receives Notice of Allowance for New Patent Covering the Combination of MN-166 (Ibudilast) and Riluzole for the Treatment of Amyotrophic Lateral Sclerosis (ALS) in Japan

MediciNova, Inc announced that it has received a Notice of Allowance from the Japan Patent Office for a pending patent application which covers the combination of ibudilast and riluzole for the treatment of ALS.
[MediciNova, Inc]
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Role of miRNAs Shuttled by Mesenchymal Stem Cell-Derived Small Extracellular Vesicles in Modulating Neuroinflammation

Investigators showed that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression.
[Scientific Reports]
Giunti, D., Marini, C., Parodi, B., Usai, C., Milanese, M., Bonanno, G., Kerlero de Rosbo, N., & Uccelli, A. (2021). Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation. Scientific Reports, 11(1), 1740. https://doi.org/10.1038/s41598-021-81039-4 Cite
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