Peptide-conjugated PMOs for the treatment of myotonic dystrophy
Antisense oligonucleotides (ASOs) have shown great therapeutic potential in the treatment of many neuromuscular diseases including myotonic dystrophy 1 (DM1). However, systemically delivered ASOs display poor biodistribution and display limited penetration into skeletal muscle. The conjugation of ce...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
Springer
2022
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| _version_ | 1797110632099610624 |
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| author | Stoodley, J Miraz, DS Jad, Y Fischer, M Wood, MJA Varela, MA |
| author2 | Maruyama, R |
| author_facet | Maruyama, R Stoodley, J Miraz, DS Jad, Y Fischer, M Wood, MJA Varela, MA |
| author_sort | Stoodley, J |
| collection | OXFORD |
| description | Antisense oligonucleotides (ASOs) have shown great therapeutic potential in the treatment of many neuromuscular diseases including myotonic dystrophy 1 (DM1). However, systemically delivered ASOs display poor biodistribution and display limited penetration into skeletal muscle. The conjugation of cell-penetrating peptides (CPPs) to phosphorodiamidate morpholino oligonucleotides (PMOs), a class of ASOs with a modified backbone, can be used to enhance ASO skeletal muscle penetration. Peptide–PMOs (P-PMOs) have been shown to be highly effective in correcting the DM1 skeletal muscle phenotype in both murine and cellular models of DM1 and at a molecular and functional level. Here we describe the synthesis and conjugation of P-PMOs and methods for analyzing their biodistribution and toxicity in the HSA-LR DM1 mouse model and their efficacy both in vitro and in vivo using FISH and RT-PCR splicing analysis. |
| first_indexed | 2024-03-07T07:57:33Z |
| format | Journal article |
| id | oxford-uuid:74e68b68-fa7d-4b2e-8867-ccb45a326466 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:57:33Z |
| publishDate | 2022 |
| publisher | Springer |
| record_format | dspace |
| spelling | oxford-uuid:74e68b68-fa7d-4b2e-8867-ccb45a3264662023-08-31T14:55:35ZPeptide-conjugated PMOs for the treatment of myotonic dystrophyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:74e68b68-fa7d-4b2e-8867-ccb45a326466EnglishSymplectic ElementsSpringer2022Stoodley, JMiraz, DSJad, YFischer, MWood, MJAVarela, MAMaruyama, RYokota, TAntisense oligonucleotides (ASOs) have shown great therapeutic potential in the treatment of many neuromuscular diseases including myotonic dystrophy 1 (DM1). However, systemically delivered ASOs display poor biodistribution and display limited penetration into skeletal muscle. The conjugation of cell-penetrating peptides (CPPs) to phosphorodiamidate morpholino oligonucleotides (PMOs), a class of ASOs with a modified backbone, can be used to enhance ASO skeletal muscle penetration. Peptide–PMOs (P-PMOs) have been shown to be highly effective in correcting the DM1 skeletal muscle phenotype in both murine and cellular models of DM1 and at a molecular and functional level. Here we describe the synthesis and conjugation of P-PMOs and methods for analyzing their biodistribution and toxicity in the HSA-LR DM1 mouse model and their efficacy both in vitro and in vivo using FISH and RT-PCR splicing analysis. |
| spellingShingle | Stoodley, J Miraz, DS Jad, Y Fischer, M Wood, MJA Varela, MA Peptide-conjugated PMOs for the treatment of myotonic dystrophy |
| title | Peptide-conjugated PMOs for the treatment of myotonic dystrophy |
| title_full | Peptide-conjugated PMOs for the treatment of myotonic dystrophy |
| title_fullStr | Peptide-conjugated PMOs for the treatment of myotonic dystrophy |
| title_full_unstemmed | Peptide-conjugated PMOs for the treatment of myotonic dystrophy |
| title_short | Peptide-conjugated PMOs for the treatment of myotonic dystrophy |
| title_sort | peptide conjugated pmos for the treatment of myotonic dystrophy |
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