Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection
Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%–3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression a...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123002755 |
| _version_ | 1827778518257238016 |
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| author | Shukkwan K. Chen Zachary C.E. Hawley Maria I. Zavodszky Sam Hana Daniel Ferretti Branka Grubor Michael Hawes Shanqin Xu Stefan Hamann Galina Marsh Patrick Cullen Ravi Challa Thomas M. Carlile Hang Zhang Wan-Hung Lee Andrea Peralta Pete Clarner Cong Wei Kathryn Koszka Feng Gao Shih-Ching Lo |
| author_facet | Shukkwan K. Chen Zachary C.E. Hawley Maria I. Zavodszky Sam Hana Daniel Ferretti Branka Grubor Michael Hawes Shanqin Xu Stefan Hamann Galina Marsh Patrick Cullen Ravi Challa Thomas M. Carlile Hang Zhang Wan-Hung Lee Andrea Peralta Pete Clarner Cong Wei Kathryn Koszka Feng Gao Shih-Ching Lo |
| author_sort | Shukkwan K. Chen |
| collection | DOAJ |
| description | Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%–3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNS-related toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy. |
| first_indexed | 2024-03-11T14:35:31Z |
| format | Article |
| id | doaj.art-5ec0da9397c241b68917b1eaa7b24e0e |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-11T14:35:31Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-5ec0da9397c241b68917b1eaa7b24e0e2023-10-31T04:09:16ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-12-0134102057Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selectionShukkwan K. Chen0Zachary C.E. Hawley1Maria I. Zavodszky2Sam Hana3Daniel Ferretti4Branka Grubor5Michael Hawes6Shanqin Xu7Stefan Hamann8Galina Marsh9Patrick Cullen10Ravi Challa11Thomas M. Carlile12Hang Zhang13Wan-Hung Lee14Andrea Peralta15Pete Clarner16Cong Wei17Kathryn Koszka18Feng Gao19Shih-Ching Lo20Biogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USACharter Preclinical Services, Hudson, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USABiogen, Cambridge, MA, USA; Corresponding author: Shih-Ching Lo, Biogen, 225 Binney Street, Cambridge, MA, USA.Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%–3% of all amyotrophic lateral sclerosis (ALS) cases. Artificial microRNAs (amiRs) delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNS-related toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy.http://www.sciencedirect.com/science/article/pii/S2162253123002755MT: oligonucleotides: therapiesadeno-associated virusALSSOD1gene therapyprimary miRNA scaffold |
| spellingShingle | Shukkwan K. Chen Zachary C.E. Hawley Maria I. Zavodszky Sam Hana Daniel Ferretti Branka Grubor Michael Hawes Shanqin Xu Stefan Hamann Galina Marsh Patrick Cullen Ravi Challa Thomas M. Carlile Hang Zhang Wan-Hung Lee Andrea Peralta Pete Clarner Cong Wei Kathryn Koszka Feng Gao Shih-Ching Lo Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection Molecular Therapy: Nucleic Acids MT: oligonucleotides: therapies adeno-associated virus ALS SOD1 gene therapy primary miRNA scaffold |
| title | Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection |
| title_full | Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection |
| title_fullStr | Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection |
| title_full_unstemmed | Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection |
| title_short | Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection |
| title_sort | efficacy and safety of a sod1 targeting artificial mirna delivered by aav9 in mice are impacted by mirna scaffold selection |
| topic | MT: oligonucleotides: therapies adeno-associated virus ALS SOD1 gene therapy primary miRNA scaffold |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123002755 |
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