A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy
Huntington’s disease (HD) is a multi-tissue failure disorder for which there is no cure. We have previously shown an effective therapeutic approach limited mainly to the central nervous system, based on a synthetic zinc finger (ZF) transcription repressor gene therapy, but it would be important to t...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1175407/full |
| _version_ | 1827965873540825088 |
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| author | Michal Mielcarek Michal Mielcarek Mark Isalan Mark Isalan |
| author_facet | Michal Mielcarek Michal Mielcarek Mark Isalan Mark Isalan |
| author_sort | Michal Mielcarek |
| collection | DOAJ |
| description | Huntington’s disease (HD) is a multi-tissue failure disorder for which there is no cure. We have previously shown an effective therapeutic approach limited mainly to the central nervous system, based on a synthetic zinc finger (ZF) transcription repressor gene therapy, but it would be important to target other tissues as well. In this study, we identify a novel minimal HSP90AB1 promoter region that can efficiently control expression not only in the CNS but also in other affected HD tissues. This promoter-enhancer is effective in driving expression of ZF therapeutic molecules in both HD skeletal muscles and the heart, in the symptomatic R6/1 mouse model. Moreover, for the first time we show that ZF molecules repressing mutant HTT reverse transcriptional pathological remodelling in HD hearts. We conclude that this HSP90AB1 minimal promoter may be used to target multiple HD organs with therapeutic genes. The new promoter has the potential to be added to the portfolio of gene therapy promoters, for use where ubiquitous expression is needed. |
| first_indexed | 2024-04-09T17:41:15Z |
| format | Article |
| id | doaj.art-f7590be16a674d96bd6d3a212d133a9f |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-09T17:41:15Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-f7590be16a674d96bd6d3a212d133a9f2023-04-17T05:46:40ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-04-011010.3389/fmolb.2023.11754071175407A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapyMichal Mielcarek0Michal Mielcarek1Mark Isalan2Mark Isalan3Department of Life Sciences, Imperial College London, London, United KingdomImperial College Centre for Synthetic Biology, Imperial College London, London, United KingdomDepartment of Life Sciences, Imperial College London, London, United KingdomImperial College Centre for Synthetic Biology, Imperial College London, London, United KingdomHuntington’s disease (HD) is a multi-tissue failure disorder for which there is no cure. We have previously shown an effective therapeutic approach limited mainly to the central nervous system, based on a synthetic zinc finger (ZF) transcription repressor gene therapy, but it would be important to target other tissues as well. In this study, we identify a novel minimal HSP90AB1 promoter region that can efficiently control expression not only in the CNS but also in other affected HD tissues. This promoter-enhancer is effective in driving expression of ZF therapeutic molecules in both HD skeletal muscles and the heart, in the symptomatic R6/1 mouse model. Moreover, for the first time we show that ZF molecules repressing mutant HTT reverse transcriptional pathological remodelling in HD hearts. We conclude that this HSP90AB1 minimal promoter may be used to target multiple HD organs with therapeutic genes. The new promoter has the potential to be added to the portfolio of gene therapy promoters, for use where ubiquitous expression is needed.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1175407/fullHuntington’s diseasemouse modelsgene therapypromoteraavzinc finger therapeutics |
| spellingShingle | Michal Mielcarek Michal Mielcarek Mark Isalan Mark Isalan A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy Frontiers in Molecular Biosciences Huntington’s disease mouse models gene therapy promoter aav zinc finger therapeutics |
| title | A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy |
| title_full | A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy |
| title_fullStr | A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy |
| title_full_unstemmed | A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy |
| title_short | A minimal region of the HSP90AB1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy |
| title_sort | minimal region of the hsp90ab1 promoter is suitable for ubiquitous expression in different somatic tissues with applicability for gene therapy |
| topic | Huntington’s disease mouse models gene therapy promoter aav zinc finger therapeutics |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1175407/full |
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