The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model

Duan, Weisong; Guo, Meijun; Le, Yi; Liu, Yakun; Li, Zhongyao; Ma, Ying; Zhang, Guisen; Liu, Yaling; Bu, Hui; Song, Xueqin; Li, Chunyan

doi:10.1038/s41434-019-0116-1

Cited by 46 publications

(30 citation statements)

References 33 publications

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“…With improvement of motor function, the average survival time of mice increased by 28–30 days ( Gaj et al, 2017 ). Similar favorable results of SOD1 deletion were reported in other animal studies as well ( Duan et al, 2020 ; Lim et al, 2020 ). Such in vivo studies were summarized in Table 1 .…”

Section: Amyotrophic Lateral Sclerosissupporting

confidence: 90%

Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions

Zhu

Yang

Hao

et al. 2021

Front. Mol. Neurosci.

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The pathogenesis of neurodegenerative diseases (NDDs) is complex and diverse. Over the decades, our understanding of NDD has been limited to pathological features. However, recent advances in gene sequencing have facilitated elucidation of NDD at a deeper level. Gene editing techniques have uncovered new genetic links to phenotypes, promoted the development of novel treatment strategies and equipped researchers with further means to construct effective cell and animal models. The current review describes the history of evolution of gene editing tools, with the aim of improving overall understanding of this technology, and focuses on the four most common NDD disorders to demonstrate the potential future applications and research directions of gene editing.

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Section: Amyotrophic Lateral Sclerosissupporting

confidence: 90%

Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions

Zhu

Yang

Hao

et al. 2021

Front. Mol. Neurosci.

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“…Matrix metalloproteinase MMP-9 is selectively expressed in fast SMN [50], whereas extracellular matrix protein Osteopontin is selectively expressed in ALS-resistant SMN [51]. Similarly, several strategies are now underway to silence the expression of mutant SOD1 as a therapeutic strategy [22,[52][53][54][55][56][57][58][59][60][61][62]. Based on our findings, there is indeed a direct correlation between the presence of misfolded SOD1 and neuronal vulnerability in the spinal cord.…”

Section: Discussionsupporting

confidence: 56%

The Timing and Extent of Motor Neuron Vulnerability in ALS Correlates with Accumulation of Misfolded SOD1 Protein in the Cortex and in the Spinal Cord

Genç¹,

Gozutok²,

Koçak³

et al. 2020

Cells

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Understanding the cellular and molecular basis of selective vulnerability has been challenging, especially for motor neuron diseases. Developing drugs that improve the health of neurons that display selective vulnerability relies on in vivo cell-based models and quantitative readout measures that translate to patient outcome. We initially developed and characterized UCHL1-eGFP mice, in which motor neurons are labeled with eGFP that is stable and long-lasting. By crossing UCHL1-eGFP to amyotrophic lateral sclerosis (ALS) disease models, we generated ALS mouse models with fluorescently labeled motor neurons. Their examination over time began to reveal the cellular basis of selective vulnerability even within the related motor neuron pools. Accumulation of misfolded SOD1 protein both in the corticospinal and spinal motor neurons over time correlated with the timing and extent of degeneration. This further proved simultaneous degeneration of both upper and lower motor neurons, and the requirement to consider both upper and lower motor neuron populations in drug discovery efforts. Demonstration of the direct correlation between misfolded SOD1 accumulation and motor neuron degeneration in both cortex and spinal cord is important for building cell-based assays in vivo. Our report sets the stage for shifting focus from mice to diseased neurons for drug discovery efforts, especially for motor neuron diseases.

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“…These results indicate that motor neurons derived from patient-specific iPSCs can be used for understanding ALS disease pathogenesis and screening therapeutic agents. In vivo gene editing of SOD1 mutations using the CRISPR-Cas9 has been studied in ALS mice, which has been shown to extend the lifespan and enhance the functions of the motor neurons [90][91][92].…”

Section: The Use Of Gene Editing For Alsmentioning

confidence: 99%

Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

Karpe

Chen

2021

Pharmaceuticals

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Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.

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The deletion of mutant SOD1 via CRISPR/Cas9/sgRNA prolongs survival in an amyotrophic lateral sclerosis mouse model

Cited by 46 publications

References 33 publications

Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions

Gene Therapy for Neurodegenerative Disease: Clinical Potential and Directions

The Timing and Extent of Motor Neuron Vulnerability in ALS Correlates with Accumulation of Misfolded SOD1 Protein in the Cortex and in the Spinal Cord

Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases

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