Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice
Friedreich’s ataxia (FA) is an inherited neurodegenerative disorder caused by decreased expression of frataxin (FXN) protein. Previous studies have shown that antisense oligonucleotides (ASOs) and single-stranded silencing RNAs can be used to increase expression of frataxin in cultured patient-deriv...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
|
| Series: | RNA Biology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15476286.2022.2043650 |
| _version_ | 1797403959750557696 |
|---|---|
| author | Audrius Kilikevicius Jun Wang Xiulong Shen Frank Rigo Thahza P. Prakash Marek Napierala David R. Corey |
| author_facet | Audrius Kilikevicius Jun Wang Xiulong Shen Frank Rigo Thahza P. Prakash Marek Napierala David R. Corey |
| author_sort | Audrius Kilikevicius |
| collection | DOAJ |
| description | Friedreich’s ataxia (FA) is an inherited neurodegenerative disorder caused by decreased expression of frataxin (FXN) protein. Previous studies have shown that antisense oligonucleotides (ASOs) and single-stranded silencing RNAs can be used to increase expression of frataxin in cultured patient-derived cells. In this study, we investigate the potential for oligonucleotides to increase frataxin expression in a mouse model for FA. After confirming successful in vivo delivery of oligonucleotides using a benchmark gapmer targeting the nuclear noncoding RNA Malat1, we tested anti-FXN oligonucleotides designed to function by various mechanisms. None of these strategies yielded enhanced expression of FXN in the model mice. Our inability to translate activation of FXN expression from cell culture to mice may be due to inadequate potency of our compounds or differences in the molecular mechanisms governing FXN gene repression and activation in FA model mice. |
| first_indexed | 2024-03-09T02:47:12Z |
| format | Article |
| id | doaj.art-4663c9e0e133444eb5e6547471e2eb50 |
| institution | Directory Open Access Journal |
| issn | 1547-6286 1555-8584 |
| language | English |
| last_indexed | 2024-03-09T02:47:12Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | RNA Biology |
| spelling | doaj.art-4663c9e0e133444eb5e6547471e2eb502023-12-05T16:09:51ZengTaylor & Francis GroupRNA Biology1547-62861555-85842022-12-0119136437210.1080/15476286.2022.20436502043650Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to miceAudrius Kilikevicius0Jun Wang1Xiulong Shen2Frank Rigo3Thahza P. Prakash4Marek Napierala5David R. Corey6UT Southwestern Medical CenterUniversity of Alabama at Birmingham, 1825 University BlvdUT Southwestern Medical CenterIonis Pharmaceuticals, Medicinal Chemistry and Antisense ResearchIonis Pharmaceuticals, Medicinal Chemistry and Antisense ResearchUniversity of Alabama at Birmingham, 1825 University BlvdUT Southwestern Medical CenterFriedreich’s ataxia (FA) is an inherited neurodegenerative disorder caused by decreased expression of frataxin (FXN) protein. Previous studies have shown that antisense oligonucleotides (ASOs) and single-stranded silencing RNAs can be used to increase expression of frataxin in cultured patient-derived cells. In this study, we investigate the potential for oligonucleotides to increase frataxin expression in a mouse model for FA. After confirming successful in vivo delivery of oligonucleotides using a benchmark gapmer targeting the nuclear noncoding RNA Malat1, we tested anti-FXN oligonucleotides designed to function by various mechanisms. None of these strategies yielded enhanced expression of FXN in the model mice. Our inability to translate activation of FXN expression from cell culture to mice may be due to inadequate potency of our compounds or differences in the molecular mechanisms governing FXN gene repression and activation in FA model mice.http://dx.doi.org/10.1080/15476286.2022.2043650friedrich’s ataxia; frataxin; antisense oligonucleotide; trinucleotide repeat |
| spellingShingle | Audrius Kilikevicius Jun Wang Xiulong Shen Frank Rigo Thahza P. Prakash Marek Napierala David R. Corey Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice RNA Biology friedrich’s ataxia; frataxin; antisense oligonucleotide; trinucleotide repeat |
| title | Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice |
| title_full | Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice |
| title_fullStr | Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice |
| title_full_unstemmed | Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice |
| title_short | Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice |
| title_sort | difficulties translating antisense mediated activation of frataxin expression from cell culture to mice |
| topic | friedrich’s ataxia; frataxin; antisense oligonucleotide; trinucleotide repeat |
| url | http://dx.doi.org/10.1080/15476286.2022.2043650 |
| work_keys_str_mv | AT audriuskilikevicius difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice AT junwang difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice AT xiulongshen difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice AT frankrigo difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice AT thahzapprakash difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice AT mareknapierala difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice AT davidrcorey difficultiestranslatingantisensemediatedactivationoffrataxinexpressionfromcellculturetomice |