Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1
Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder, caused by expansion of a CTG microsatellite repeat in the 3ʹ untranslated region of the DMPK (dystrophia myotonica protein kinase) gene. To date, novel therapeutic approaches have focused on transient suppression of the mutant...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2020
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| _version_ | 1826277812269481984 |
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| author | Marsh, S Hanson, B Wood, MJA Varela, MA Roberts, TC |
| author_facet | Marsh, S Hanson, B Wood, MJA Varela, MA Roberts, TC |
| author_sort | Marsh, S |
| collection | OXFORD |
| description | Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder, caused by expansion of a CTG microsatellite repeat in the 3ʹ untranslated region of the DMPK (dystrophia myotonica protein kinase) gene. To date, novel therapeutic approaches have focused on transient suppression of the mutant, repeat-expanded RNA. However, recent developments in the field of genome editing have raised the exciting possibility of inducing permanent correction of the DM1 genetic defect. Specifically, repurposing of the prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system has enabled programmable, site-specific, and multiplex genome editing. CRISPR-based strategies for the treatment of DM1 can be applied either directly to patients, or indirectly through the ex vivo modification of patient-derived cells, and they include excision of the repeat expansion, insertion of synthetic polyadenylation signals upstream of the repeat, steric interference with RNA polymerase II procession through the repeat leading to transcriptional downregulation of DMPK, and direct RNA targeting of the mutant RNA species. Potential obstacles to such therapies are discussed, including the major challenge of Cas9 and guide RNA transgene/ribonuclear protein delivery, off-target gene editing, vector genome insertion at cut sites, on-target unintended mutagenesis (e.g., repeat inversion), pre-existing immunity to Cas9 or AAV antigens, immunogenicity, and Cas9 persistence. |
| first_indexed | 2024-03-06T23:34:32Z |
| format | Journal article |
| id | oxford-uuid:6d328483-e261-451c-9054-01bb58604516 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:34:32Z |
| publishDate | 2020 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:6d328483-e261-451c-9054-01bb586045162022-03-26T19:16:16ZApplication of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6d328483-e261-451c-9054-01bb58604516EnglishSymplectic ElementsCell Press2020Marsh, SHanson, BWood, MJAVarela, MARoberts, TCMyotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder, caused by expansion of a CTG microsatellite repeat in the 3ʹ untranslated region of the DMPK (dystrophia myotonica protein kinase) gene. To date, novel therapeutic approaches have focused on transient suppression of the mutant, repeat-expanded RNA. However, recent developments in the field of genome editing have raised the exciting possibility of inducing permanent correction of the DM1 genetic defect. Specifically, repurposing of the prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system has enabled programmable, site-specific, and multiplex genome editing. CRISPR-based strategies for the treatment of DM1 can be applied either directly to patients, or indirectly through the ex vivo modification of patient-derived cells, and they include excision of the repeat expansion, insertion of synthetic polyadenylation signals upstream of the repeat, steric interference with RNA polymerase II procession through the repeat leading to transcriptional downregulation of DMPK, and direct RNA targeting of the mutant RNA species. Potential obstacles to such therapies are discussed, including the major challenge of Cas9 and guide RNA transgene/ribonuclear protein delivery, off-target gene editing, vector genome insertion at cut sites, on-target unintended mutagenesis (e.g., repeat inversion), pre-existing immunity to Cas9 or AAV antigens, immunogenicity, and Cas9 persistence. |
| spellingShingle | Marsh, S Hanson, B Wood, MJA Varela, MA Roberts, TC Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1 |
| title | Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1 |
| title_full | Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1 |
| title_fullStr | Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1 |
| title_full_unstemmed | Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1 |
| title_short | Application of CRISPR-Cas9-mediated genome editing for the treatment of myotonic dystrophy type 1 |
| title_sort | application of crispr cas9 mediated genome editing for the treatment of myotonic dystrophy type 1 |
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