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Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD

Hanson, Britt (författare)
Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England.;Univ Oxford, Dept Physiol Anat & Genet, South Parks Rd, Oxford OX1 3QX, England.
Stenler, Sofia, 1980- (författare)
Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Univ Oxford, Dept Physiol Anat & Genet, South Parks Rd, Oxford OX1 3QX, England
Ahlskog, Nina (författare)
Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England.;Univ Oxford, Inst Dev & Regenerat Med, IMS Tetsuya Nakamura Bldg,Old Rd Campus,Roosevelt, Oxford OX3 7TY, England.
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Chwalenia, Katarzyna (författare)
Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England.;Univ Oxford, Inst Dev & Regenerat Med, IMS Tetsuya Nakamura Bldg,Old Rd Campus,Roosevelt, Oxford OX3 7TY, England.
Svrzikapa, Nenad (författare)
Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England.;Univ Oxford, Inst Dev & Regenerat Med, IMS Tetsuya Nakamura Bldg,Old Rd Campus,Roosevelt, Oxford OX3 7TY, England.;Wave Life Sci Ltd, Cambridge, MA 02138 USA.
Coenen-Stass, Anna M. L. (författare)
Univ Oxford, Dept Physiol Anat & Genet, South Parks Rd, Oxford OX1 3QX, England.;Merck KGaA, Frankfurter Str 250, D-64293 Darmstadt, Germany.
Weinberg, Marc S. (författare)
Univ Witwatersrand, Dept Mol Med & Haematol, Antiviral Gene Therapy Res Unit, Med Sch, ZA-2050 Johannesburg, South Africa.;Asklepios BioPharmaceut Inc, Res Triangle Pk, NC 27709 USA.
Wood, Matthew J. A. (författare)
Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England.;Univ Oxford, Inst Dev & Regenerat Med, IMS Tetsuya Nakamura Bldg,Old Rd Campus,Roosevelt, Oxford OX3 7TY, England.;MDUK Oxford Neuromuscular Ctr, South Parks Rd, Oxford OX1 3QX, England.
Roberts, Thomas C. (författare)
Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England.;Univ Oxford, Inst Dev & Regenerat Med, IMS Tetsuya Nakamura Bldg,Old Rd Campus,Roosevelt, Oxford OX3 7TY, England.;MDUK Oxford Neuromuscular Ctr, South Parks Rd, Oxford OX1 3QX, England.
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Univ Oxford, Dept Paediat, South Parks Rd, Oxford OX1 3QX, England;Univ Oxford, Dept Physiol Anat & Genet, South Parks Rd, Oxford OX1 3QX, England. Institutionen för farmaceutisk biovetenskap (creator_code:org_t)
Elsevier, 2022
2022
Engelska.
Ingår i: Molecular Therapy Nucleic Acids. - : Elsevier. - 2162-2531. ; 30, s. 379-397
Relaterad länk:
https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • Duchenne muscular dystrophy (DMD) is the most prevalent inherited myopathy affecting children, caused by genetic loss of the gene encoding the dystrophin protein. Here we have investigated the use of the Staphylococcus aureus CRISPR-Cas9 system and a double-cut strategy, delivered using a pair of adeno-associated virus serotype 9 (AAV9) vectors, for dystrophin restoration in the severely affected dystrophin/utrophin double-knockout (dKO) mouse. Single guide RNAs were designed to excise Dmd exon 23, with flanking intronic regions repaired by non-homologous end joining. Exon 23 deletion was confirmed at the DNA level by PCR and Sanger sequencing, and at the RNA level by RT-qPCR. Restoration of dystrophin protein expression was demonstrated by western blot and immunofluorescence staining in mice treated via either intraperitoneal or intravenous routes of delivery. Dystrophin restoration was most effective in the diaphragm, where a maximum of 5.7% of wild-type dystrophin expression was observed. CRISPR treatment was insufficient to extend lifespan in the dKO mouse, and dystrophin was expressed in a within-fiber patchy manner in skeletal muscle tissues. Further analysis revealed a plethora of non-productive DNA repair events, including AAV genome integration at the CRISPR cut sites. This study highlights potential challenges for the successful development of CRISPR therapies in the context of DMD.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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