FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3111686026> ?p ?o ?g. }

• W3111686026 endingPage "311" @default.
• W3111686026 startingPage "298" @default.
• W3111686026 abstract "Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete silencing of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Previously, we showed that CRISPR inhibition could successfully target and repress DUX4 in FSHD myocytes. However, an effective therapy will require both efficient delivery of therapeutic components to skeletal muscles and long-term repression of the disease locus. Thus, we re-engineered our platform to allow in vivo delivery of more potent epigenetic repressors. We designed an FSHD-optimized regulatory cassette to drive skeletal muscle-specific expression of dCas9 from Staphylococcus aureus fused to HP1α, HP1γ, the MeCP2 transcriptional repression domain, or the SUV39H1 SET domain. Targeting each regulator to the DUX4 promoter/exon 1 increased chromatin repression at the locus, specifically suppressing DUX4 and its target genes in FSHD myocytes and in a mouse model of the disease. Importantly, minimizing the regulatory cassette and using the smaller Cas9 ortholog allowed our therapeutic cassettes to be effectively packaged into adeno-associated virus (AAV) vectors for in vivo delivery. By engineering a muscle-specific epigenetic CRISPR platform compatible with AAV vectors for gene therapy, we have laid the groundwork for clinical use of dCas9-based chromatin effectors in skeletal muscle disorders. Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete silencing of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Previously, we showed that CRISPR inhibition could successfully target and repress DUX4 in FSHD myocytes. However, an effective therapy will require both efficient delivery of therapeutic components to skeletal muscles and long-term repression of the disease locus. Thus, we re-engineered our platform to allow in vivo delivery of more potent epigenetic repressors. We designed an FSHD-optimized regulatory cassette to drive skeletal muscle-specific expression of dCas9 from Staphylococcus aureus fused to HP1α, HP1γ, the MeCP2 transcriptional repression domain, or the SUV39H1 SET domain. Targeting each regulator to the DUX4 promoter/exon 1 increased chromatin repression at the locus, specifically suppressing DUX4 and its target genes in FSHD myocytes and in a mouse model of the disease. Importantly, minimizing the regulatory cassette and using the smaller Cas9 ortholog allowed our therapeutic cassettes to be effectively packaged into adeno-associated virus (AAV) vectors for in vivo delivery. By engineering a muscle-specific epigenetic CRISPR platform compatible with AAV vectors for gene therapy, we have laid the groundwork for clinical use of dCas9-based chromatin effectors in skeletal muscle disorders." @default.
• W3111686026 created "2020-12-21" @default.
• W3111686026 creator A5010232240 @default.
• W3111686026 creator A5041875123 @default.
• W3111686026 date "2021-03-01" @default.
• W3111686026 modified "2023-10-06" @default.
• W3111686026 title "Targeted epigenetic repression by CRISPR/dSaCas9 suppresses pathogenic DUX4-fl expression in FSHD" @default.
• W3111686026 cites W1486257535 @default.
• W3111686026 cites W1546225709 @default.
• W3111686026 cites W1784857457 @default.
• W3111686026 cites W1963527872 @default.
• W3111686026 cites W1964930281 @default.
• W3111686026 cites W1967915464 @default.
• W3111686026 cites W1975986396 @default.
• W3111686026 cites W2003975348 @default.
• W3111686026 cites W2018380248 @default.
• W3111686026 cites W2023284422 @default.
• W3111686026 cites W2024736438 @default.
• W3111686026 cites W2026556066 @default.
• W3111686026 cites W2027933092 @default.
• W3111686026 cites W2029244267 @default.
• W3111686026 cites W2037275396 @default.
• W3111686026 cites W2037293161 @default.
• W3111686026 cites W2037298558 @default.
• W3111686026 cites W2037761873 @default.
• W3111686026 cites W2038856813 @default.
• W3111686026 cites W2065380345 @default.
• W3111686026 cites W2065979540 @default.
• W3111686026 cites W2070614858 @default.
• W3111686026 cites W2073229191 @default.
• W3111686026 cites W2073334751 @default.
• W3111686026 cites W2075704285 @default.
• W3111686026 cites W2076732839 @default.
• W3111686026 cites W2081357269 @default.
• W3111686026 cites W2082127114 @default.
• W3111686026 cites W2088292638 @default.
• W3111686026 cites W2095426368 @default.
• W3111686026 cites W2101092089 @default.
• W3111686026 cites W2108922768 @default.
• W3111686026 cites W2110029186 @default.
• W3111686026 cites W2121242557 @default.
• W3111686026 cites W2122644537 @default.
• W3111686026 cites W2127114672 @default.
• W3111686026 cites W2141452262 @default.
• W3111686026 cites W2147775310 @default.
• W3111686026 cites W2150114997 @default.
• W3111686026 cites W2150374310 @default.
• W3111686026 cites W2153811661 @default.
• W3111686026 cites W2169464461 @default.
• W3111686026 cites W2172706654 @default.
• W3111686026 cites W2191094967 @default.
• W3111686026 cites W2203460689 @default.
• W3111686026 cites W2224398381 @default.
• W3111686026 cites W2238012416 @default.
• W3111686026 cites W2239511084 @default.
• W3111686026 cites W2279061421 @default.
• W3111686026 cites W2279497235 @default.
• W3111686026 cites W2290067868 @default.
• W3111686026 cites W2345624975 @default.
• W3111686026 cites W2398889972 @default.
• W3111686026 cites W2402426153 @default.
• W3111686026 cites W2414202394 @default.
• W3111686026 cites W2511930191 @default.
• W3111686026 cites W2522031854 @default.
• W3111686026 cites W2558046424 @default.
• W3111686026 cites W2726053863 @default.
• W3111686026 cites W2730980172 @default.
• W3111686026 cites W2751709410 @default.
• W3111686026 cites W2771262431 @default.
• W3111686026 cites W2793309516 @default.
• W3111686026 cites W2794191764 @default.
• W3111686026 cites W2802326506 @default.
• W3111686026 cites W2802615273 @default.
• W3111686026 cites W2804231890 @default.
• W3111686026 cites W2808487038 @default.
• W3111686026 cites W2810159725 @default.
• W3111686026 cites W2897468238 @default.
• W3111686026 cites W2900510405 @default.
• W3111686026 cites W2906523411 @default.
• W3111686026 cites W2918808095 @default.
• W3111686026 cites W2942248063 @default.
• W3111686026 cites W2947753241 @default.
• W3111686026 cites W2951577426 @default.
• W3111686026 cites W2957134350 @default.
• W3111686026 cites W2964288853 @default.
• W3111686026 cites W2974053118 @default.
• W3111686026 cites W2979046344 @default.
• W3111686026 cites W2989928744 @default.
• W3111686026 cites W3015374806 @default.
• W3111686026 cites W3037746690 @default.
• W3111686026 cites W3098554493 @default.
• W3111686026 doi "https://doi.org/10.1016/j.omtm.2020.12.001" @default.
• W3111686026 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7806950" @default.
• W3111686026 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33511244" @default.
• W3111686026 hasPublicationYear "2021" @default.
• W3111686026 type Work @default.
• W3111686026 sameAs 3111686026 @default.
• W3111686026 citedByCount "20" @default.

• next