Base editing-mediated splicing correction therapy for spinal muscular atrophy

Lin, Xinhua; Chen, Haizhu; Lu, Ying‐Qian; Hong, Shunyan; Hu, Xin; Gao, Yanxia; Lai, Lu-Lu; Li, Jinjing; Wang, Zishuai; Ying, Weiwen; Ma, Lixiang; Wang, Ning; Zuo, Erwei; Yang, Hui; Chen, Wan‐Jin

doi:10.1038/s41422-020-0304-y

Cited by 36 publications

(37 citation statements)

References 11 publications

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“…41 To avoid unpredictable mutations generated by designer nucleases, a BE strategy has been explored recently. 42 In particular, Lin and colleagues 42 used ABEs to target exonic splicing silencer A (ESS-A; containing the C-to-T transition in position 6 of wild-type SMN2) or ESS-B in exon 7 of SMN2 in SMA iPSCs (Figure 1C). Targeting of ESS-A led to several mutations, including reversion of the C-to-T transition in position 6.…”

Section: Genome Editing Strategies For Smamentioning

confidence: 99%

“…Interestingly, this missense transition not only restored splicing but was also effective in ameliorating the cellular phenotype of iPSCderived motor neurons and prolonging the lifespan and improving the phenotype of germline-edited SMA mice. 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).…”

Section: Genome Editing Strategies For Smamentioning

confidence: 99%

“…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%

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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%

Section: Genome Editing Strategies For Smamentioning

confidence: 99%

Section: Genome Editing Strategies For Smamentioning

confidence: 99%

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

et al. 2022

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“…17 Genome editing techniques have also been used to disrupt SMN2 intronic splicing silencers to successfully restore SMN function in mice models of spinal muscular atrophy and patient derived induced pluripotent stem cells. 18 Additionally, there are exciting recent examples of using of a patient derived oligonucleotide treatment for neuronal ceroid lipofuscinosis 7, suggesting that personalised treatment of monogenic neurological disorders is possible. 19 Use of these techniques could facilitate treatment of many monogenic neurological disorders in future and end the traditional view that they are incurable.…”

Section: Linking Pathological Mechanisms To Common Neurological Disormentioning

confidence: 99%

“…More recently, the FDA approved a therapy that uses an adeno-associated virus to deliver complementary DNA encoding a functional SMN gene, which effectively restores motor function 17. Genome editing techniques have also been used to disrupt SMN2 intronic splicing silencers to successfully restore SMN function in mice models of spinal muscular atrophy and patient derived induced pluripotent stem cells 18. Additionally, there are exciting recent examples of using of a patient derived oligonucleotide treatment for neuronal ceroid lipofuscinosis 7, suggesting that personalised treatment of monogenic neurological disorders is possible 19.…”

Section: Disease Models For Translating Gene Therapies To Preserve Brmentioning

confidence: 99%

Rethinking monogenic neurological diseases

Chen

Cheng

et al. 2020

BMJ

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Rethinking monogenic neurological diseases Studies on monogenic diseases can provide valuable insights into the mechanisms of other neurological disorders, say Wan-Jin Chen and colleagues This article is part of a series launched at the Chinese Stroke Association annual conference on 10 October 2020, Beijing, China. Open access fees were funded by the National Science and Technology Major Project. The BMJ peer reviewed, edited, and made the decision to publish these articles.

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A modified glycosylase base editor without predictable DNA off‐target effects

Lian,

Chen,

Chen

et al. 2024

FEBS Letters

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Glycosylase base editor (GBE) can induce C‐to‐G transversion in mammalian cells, showing great promise for the treatment of human genetic disorders. However, the limited efficiency of transversion and the possibility of off‐target effects caused by Cas9 restrict its potential clinical applications. In our recent study, we have successfully developed TaC9‐CBE and TaC9‐ABE by separating nCas9 and deaminase, which eliminates the Cas9‐dependent DNA off‐target effects without compromising editing efficiency. We developed a novel GBE called TaC9‐GBEYE1, which utilizes the deaminase and UNG‐nCas9 guided by TALE and sgRNA, respectively. TaC9‐GBEYE1 showed comparable levels of on‐target editing efficiency to traditional GBE at 19 target sites, without any off‐target effects caused by Cas9 or TALE. The TaC9‐GBEYE1 is a safe tool for gene therapy.

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Base editing-mediated splicing correction therapy for spinal muscular atrophy

Cited by 36 publications

References 11 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

Rethinking monogenic neurological diseases

A modified glycosylase base editor without predictable DNA off‐target effects

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