CRISPR/Cas9-Mediated Gene Correction to Understand ALS

Yun, Young; Ha, You Jung

doi:10.3390/ijms21113801

Cited by 38 publications

(29 citation statements)

References 85 publications

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“…42 Furthermore, targeting of ESS-B led to generation of the synonymous A36G mutation, which ameliorated the cellular phenotype of SMA iPSC-derived motor neurons. 42 Genome editing strategies for ALS HDR-based genome editing approaches have been used to correct a variety of SOD1 mutations in iPSCs from individuals with ALS (reviewed in Yun and Ha 43 ), demonstrating rescue of the ALS cellular phenotype in motor neurons derived from gene-corrected iPSCs (Figure 1D). Similar approaches have been exploited in iPSCs from people with mutations in FUS and TARDBP.…”

Section: Genome Editing Strategies For Smamentioning

confidence: 99%

Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

et al. 2022

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Motor neuron diseases are untreatable with common pharmacological approaches. Spinal muscular atrophy (SMA) is caused by SMN1 gene mutations leading to lowered SMN expression. Symptoms are alleviated in infants with a higher copy number of the SMN2 gene, which, however, displays a splicing defect resulting in low SMN levels. Amyotrophic lateral sclerosis (ALS) is caused by a number of mutations, with C9orf72 repeat expansions the most common genetic cause and SOD1 gain-of-function mutations the first genetic cause identified for this disease. Genetic therapies based on oligonucleotides that enhance SMN2 splicing and SMN production or lower SOD1 expression have shown promise in initial clinical trials for individuals with SMA and ALS harboring SOD1 mutations, respectively. Gene addition/silencing approaches using adeno-associated viruses (AAVs) are also currently under clinical investigation in trials for SMA and ALS. Here we provide a brief overview of these efforts and their advantages and challenges. We also review genome editing approaches aimed at correcting the diseasecausing mutations or modulating the expression of genetic modifiers, e.g., by repairing SOD1 mutations or the SMN2 splicing defect or deleting C9orf72 expanded repeats. These studies have shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders.Both of these major neurological diseases lead to a severe handicap and cause early mortality in the majority of affected people. These disorders are currently untreatable with common pharmacological approaches. On the other hand, genetic therapy has been quite promising in early clinical trials, particularly for SMA. 16,17 Here we provide a brief overview of these initial therapeutic strategies and cover the pre-clinical studies exploiting genome editing approaches and their challenges and advantages.

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Section: Genome Editing Strategies For Smamentioning

confidence: 99%

Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

et al. 2022

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“…Clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) genome editing: CRISPR/Cas9 can delete a copy of Ku80 (DNA repair protein) in C9orf72 iPSCs, leading to the decrease in Ku80 expression and pro-apoptotic protein levels. Thus, CRISPR/Cas9 approach can be used for C9orf72 repeat expansion to verify the pathological phenotype in patient-derived iPSCs and to determine gene-based therapies [182]. Studies have shown that once SOD1 gene is deleted, adeno-associated virus 9-Staphylococcus aureus Cas9-single guide RNA5 (AAV9-SaCas9-sgRNA5) will increase survival of SOD1 G93A mice by 54.6%, and significantly improve the performance of ALS transgenic mice.…”

Section: Gene Therapiesmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies

Yang

Wang

et al. 2021

Antioxidants

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.

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“…With the application of CRISPR/Cas9 technology, isogenic iPSCs can be generated, allowing to exclusively focus on the specific disease-causing mutation [56], and to demonstrate a rescue of the disease-related cellular endophenotype. Isogenic iPSCs obtained by mutation correction in genes have been generated to rescue the ALS phenotype [57]. In another study, mutated dystrophin was successfully corrected in an iPSC model of Duchenne muscular dystrophy [58].…”

Section: Gene Editing-crispr-cas9 Technologymentioning

confidence: 99%

Induced Pluripotent Stem Cells (iPSCs) and Gene Therapy: A New Era for the Treatment of Neurological Diseases

Sguazzi

Muto

Tartaglia

et al. 2021

IJMS

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To date, gene therapy has employed viral vectors to deliver therapeutic genes. However, recent progress in molecular and cell biology has revolutionized the field of stem cells and gene therapy. A few years ago, clinical trials started using stem cell replacement therapy, and the induced pluripotent stem cells (iPSCs) technology combined with CRISPR-Cas9 gene editing has launched a new era in gene therapy for the treatment of neurological disorders. Here, we summarize the latest findings in this research field and discuss their clinical applications, emphasizing the relevance of recent studies in the development of innovative stem cell and gene editing therapeutic approaches. Even though tumorigenicity and immunogenicity are existing hurdles, we report how recent progress has tackled them, making engineered stem cell transplantation therapy a realistic option.

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CRISPR/Cas9-Mediated Gene Correction to Understand ALS

Cited by 38 publications

References 85 publications

Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies

Induced Pluripotent Stem Cells (iPSCs) and Gene Therapy: A New Era for the Treatment of Neurological Diseases

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