Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117301304 |
| _version_ | 1817969946603290624 |
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| author | Lindsay M. Wallace Nizar Y. Saad Nettie K. Pyne Allison M. Fowler Jocelyn O. Eidahl Jacqueline S. Domire Danielle A. Griffin Adam C. Herman Zarife Sahenk Louise R. Rodino-Klapac Scott Q. Harper |
| author_facet | Lindsay M. Wallace Nizar Y. Saad Nettie K. Pyne Allison M. Fowler Jocelyn O. Eidahl Jacqueline S. Domire Danielle A. Griffin Adam C. Herman Zarife Sahenk Louise R. Rodino-Klapac Scott Q. Harper |
| author_sort | Lindsay M. Wallace |
| collection | DOAJ |
| description | RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy. |
| first_indexed | 2024-04-13T20:27:54Z |
| format | Article |
| id | doaj.art-a85b27f6001d49549c5557e9c633b735 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-13T20:27:54Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-a85b27f6001d49549c5557e9c633b7352022-12-22T02:31:16ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012018-03-018C12113010.1016/j.omtm.2017.12.005Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHDLindsay M. Wallace0Nizar Y. Saad1Nettie K. Pyne2Allison M. Fowler3Jocelyn O. Eidahl4Jacqueline S. Domire5Danielle A. Griffin6Adam C. Herman7Zarife Sahenk8Louise R. Rodino-Klapac9Scott Q. Harper10Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USAResearch Information Solutions and Innovation Infrastructure, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USARNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy.http://www.sciencedirect.com/science/article/pii/S2329050117301304gene therapyRNA interferenceRNAiadeno-associated viral vectorsAAVfacioscapulohumeral muscular dystrophyFSHDDUX4microRNA |
| spellingShingle | Lindsay M. Wallace Nizar Y. Saad Nettie K. Pyne Allison M. Fowler Jocelyn O. Eidahl Jacqueline S. Domire Danielle A. Griffin Adam C. Herman Zarife Sahenk Louise R. Rodino-Klapac Scott Q. Harper Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD Molecular Therapy: Methods & Clinical Development gene therapy RNA interference RNAi adeno-associated viral vectors AAV facioscapulohumeral muscular dystrophy FSHD DUX4 microRNA |
| title | Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD |
| title_full | Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD |
| title_fullStr | Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD |
| title_full_unstemmed | Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD |
| title_short | Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD |
| title_sort | pre clinical safety and off target studies to support translation of aav mediated rnai therapy for fshd |
| topic | gene therapy RNA interference RNAi adeno-associated viral vectors AAV facioscapulohumeral muscular dystrophy FSHD DUX4 microRNA |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117301304 |
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