Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane
Abstract The round window of the cochlea provides an ideal route for delivering medicines and gene therapy reagents that can cross the round window membrane (RWM) into the inner ear. Recombinant adeno‐associated viruses (rAAVs) have several advantages and are recommended as viral vectors for gene tr...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-01-01
|
| Series: | Bioengineering & Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/btm2.10189 |
| _version_ | 1818366646844129280 |
|---|---|
| author | Zhen Zhang Zhengnong Chen Liqiang Fan Thomas Landry Jeremy Brown Zhiping Yu Shankai Yin Jian Wang |
| author_facet | Zhen Zhang Zhengnong Chen Liqiang Fan Thomas Landry Jeremy Brown Zhiping Yu Shankai Yin Jian Wang |
| author_sort | Zhen Zhang |
| collection | DOAJ |
| description | Abstract The round window of the cochlea provides an ideal route for delivering medicines and gene therapy reagents that can cross the round window membrane (RWM) into the inner ear. Recombinant adeno‐associated viruses (rAAVs) have several advantages and are recommended as viral vectors for gene transfection. However, rAAVs cannot cross an intact RWM. Consequently, ultrasound‐mediated microbubble (USMB) cavitation is potentially useful, because it can sonoporate the cell membranes, and increase their permeability to large molecules. The use of USMB cavitation for drug delivery across the RWM has been tested in a few animal studies but has not been used in the context of AAV‐mediated gene transfection. The currently available large size of the ultrasound probe appears to be a limiting factor in the application of this method to the RWM. In this study, we used home‐made ultrasound probe with a decreased diameter to 1.5 mm, which enabled the easy positioning of the probe close to the RWM. In guinea pigs, we used this probe to determine that (1) USMB cavitation caused limited damage to the outer surface layer or the RWM, (2) an eGFP‐gene carrying rAAV could effectively pass the USMB‐treated RWM and reliably transfect cochlear cells, and (3) the hearing function of the cochlea remained unchanged. Our results suggest that USMB cavitation of the RWM is a good method for rAAV‐mediated cochlear gene transfection with clear potential for clinical translation. We additionally discuss several advantages of the small probe size. |
| first_indexed | 2024-12-13T22:39:28Z |
| format | Article |
| id | doaj.art-348ffa3ede6f40b4aa9b06292a016c89 |
| institution | Directory Open Access Journal |
| issn | 2380-6761 |
| language | English |
| last_indexed | 2024-12-13T22:39:28Z |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Bioengineering & Translational Medicine |
| spelling | doaj.art-348ffa3ede6f40b4aa9b06292a016c892022-12-21T23:28:53ZengWileyBioengineering & Translational Medicine2380-67612021-01-0161n/an/a10.1002/btm2.10189Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membraneZhen Zhang0Zhengnong Chen1Liqiang Fan2Thomas Landry3Jeremy Brown4Zhiping Yu5Shankai Yin6Jian Wang7Otolaryngology Research Institute, 6th Affiliated Hospital Jiao Tong University Shanghai ChinaOtolaryngology Research Institute, 6th Affiliated Hospital Jiao Tong University Shanghai ChinaOtolaryngology Research Institute, 6th Affiliated Hospital Jiao Tong University Shanghai ChinaSchool of Biomedical Engineering Dalhousie University Halifax CanadaSchool of Biomedical Engineering Dalhousie University Halifax CanadaSchool of Communication Science and Disorders Dalhousie University Halifax CanadaOtolaryngology Research Institute, 6th Affiliated Hospital Jiao Tong University Shanghai ChinaSchool of Communication Science and Disorders Dalhousie University Halifax CanadaAbstract The round window of the cochlea provides an ideal route for delivering medicines and gene therapy reagents that can cross the round window membrane (RWM) into the inner ear. Recombinant adeno‐associated viruses (rAAVs) have several advantages and are recommended as viral vectors for gene transfection. However, rAAVs cannot cross an intact RWM. Consequently, ultrasound‐mediated microbubble (USMB) cavitation is potentially useful, because it can sonoporate the cell membranes, and increase their permeability to large molecules. The use of USMB cavitation for drug delivery across the RWM has been tested in a few animal studies but has not been used in the context of AAV‐mediated gene transfection. The currently available large size of the ultrasound probe appears to be a limiting factor in the application of this method to the RWM. In this study, we used home‐made ultrasound probe with a decreased diameter to 1.5 mm, which enabled the easy positioning of the probe close to the RWM. In guinea pigs, we used this probe to determine that (1) USMB cavitation caused limited damage to the outer surface layer or the RWM, (2) an eGFP‐gene carrying rAAV could effectively pass the USMB‐treated RWM and reliably transfect cochlear cells, and (3) the hearing function of the cochlea remained unchanged. Our results suggest that USMB cavitation of the RWM is a good method for rAAV‐mediated cochlear gene transfection with clear potential for clinical translation. We additionally discuss several advantages of the small probe size.https://doi.org/10.1002/btm2.10189cochleacochlear gene therapygene deliveryGuinea pigsrecombinant adeno‐associated virusround window membrane |
| spellingShingle | Zhen Zhang Zhengnong Chen Liqiang Fan Thomas Landry Jeremy Brown Zhiping Yu Shankai Yin Jian Wang Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane Bioengineering & Translational Medicine cochlea cochlear gene therapy gene delivery Guinea pigs recombinant adeno‐associated virus round window membrane |
| title | Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane |
| title_full | Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane |
| title_fullStr | Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane |
| title_full_unstemmed | Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane |
| title_short | Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane |
| title_sort | ultrasound microbubble cavitation facilitates adeno associated virus mediated cochlear gene transfection across the round window membrane |
| topic | cochlea cochlear gene therapy gene delivery Guinea pigs recombinant adeno‐associated virus round window membrane |
| url | https://doi.org/10.1002/btm2.10189 |
| work_keys_str_mv | AT zhenzhang ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT zhengnongchen ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT liqiangfan ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT thomaslandry ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT jeremybrown ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT zhipingyu ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT shankaiyin ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane AT jianwang ultrasoundmicrobubblecavitationfacilitatesadenoassociatedvirusmediatedcochleargenetransfectionacrosstheroundwindowmembrane |