Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice. / Mathiesen, Barbara K.; Miyakoshi, Leo M.; Cederroth, Christopher R.; Tserga, Evangelia; Versteegh, Corstiaen; Bork, Peter A.R.; Hauglund, Natalie L.; Gomolka, Ryszard Stefan; Mori, Yuki; Edvall, Niklas K.; Rouse, Stephanie; Møllgård, Kjeld; Holt, Jeffrey R.; Nedergaard, Maiken; Canlon, Barbara.

In: Science Translational Medicine, Vol. 15, No. 702, eabq3916, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Mathiesen, BK, Miyakoshi, LM, Cederroth, CR, Tserga, E, Versteegh, C, Bork, PAR, Hauglund, NL, Gomolka, RS, Mori, Y, Edvall, NK, Rouse, S, Møllgård, K, Holt, JR, Nedergaard, M & Canlon, B 2023, 'Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice', Science Translational Medicine, vol. 15, no. 702, eabq3916. https://doi.org/10.1126/scitranslmed.abq3916

APA

Mathiesen, B. K., Miyakoshi, L. M., Cederroth, C. R., Tserga, E., Versteegh, C., Bork, P. A. R., Hauglund, N. L., Gomolka, R. S., Mori, Y., Edvall, N. K., Rouse, S., Møllgård, K., Holt, J. R., Nedergaard, M., & Canlon, B. (2023). Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice. Science Translational Medicine, 15(702), [eabq3916]. https://doi.org/10.1126/scitranslmed.abq3916

Vancouver

Mathiesen BK, Miyakoshi LM, Cederroth CR, Tserga E, Versteegh C, Bork PAR et al. Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice. Science Translational Medicine. 2023;15(702). eabq3916. https://doi.org/10.1126/scitranslmed.abq3916

Author

Mathiesen, Barbara K. ; Miyakoshi, Leo M. ; Cederroth, Christopher R. ; Tserga, Evangelia ; Versteegh, Corstiaen ; Bork, Peter A.R. ; Hauglund, Natalie L. ; Gomolka, Ryszard Stefan ; Mori, Yuki ; Edvall, Niklas K. ; Rouse, Stephanie ; Møllgård, Kjeld ; Holt, Jeffrey R. ; Nedergaard, Maiken ; Canlon, Barbara. / Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice. In: Science Translational Medicine. 2023 ; Vol. 15, No. 702.

Bibtex

@article{306736bbae4b4fbf991febe20e5a8b5a,

title = "Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice",

abstract = "Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy showed that large-particle tracers injected into the cerebrospinal fluid reached the inner ear by dispersive transport via the cochlear aqueduct in adult mice. A single intracisternal injection of adeno-associated virus carrying solute carrier family 17, member 8 (Slc17A8), which encodes vesicular glutamate transporter-3 (VGLUT3), rescued hearing in adult deaf Slc17A8−/− mice by restoring VGLUT3 protein expression in inner hair cells, with minimal ectopic expression in the brain and none in the liver. Our findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step toward using gene therapy to restore hearing in humans.",

author = "Mathiesen, {Barbara K.} and Miyakoshi, {Leo M.} and Cederroth, {Christopher R.} and Evangelia Tserga and Corstiaen Versteegh and Bork, {Peter A.R.} and Hauglund, {Natalie L.} and Gomolka, {Ryszard Stefan} and Yuki Mori and Edvall, {Niklas K.} and Stephanie Rouse and Kjeld M{\o}llg{\aa}rd and Holt, {Jeffrey R.} and Maiken Nedergaard and Barbara Canlon",

year = "2023",

doi = "10.1126/scitranslmed.abq3916",

language = "English",

volume = "15",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "american association for the advancement of science",

number = "702",

}

RIS

TY - JOUR

T1 - Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

AU - Mathiesen, Barbara K.

AU - Miyakoshi, Leo M.

AU - Cederroth, Christopher R.

AU - Tserga, Evangelia

AU - Versteegh, Corstiaen

AU - Bork, Peter A.R.

AU - Hauglund, Natalie L.

AU - Gomolka, Ryszard Stefan

AU - Mori, Yuki

AU - Edvall, Niklas K.

AU - Rouse, Stephanie

AU - Møllgård, Kjeld

AU - Holt, Jeffrey R.

AU - Nedergaard, Maiken

AU - Canlon, Barbara

PY - 2023

Y1 - 2023

N2 - Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy showed that large-particle tracers injected into the cerebrospinal fluid reached the inner ear by dispersive transport via the cochlear aqueduct in adult mice. A single intracisternal injection of adeno-associated virus carrying solute carrier family 17, member 8 (Slc17A8), which encodes vesicular glutamate transporter-3 (VGLUT3), rescued hearing in adult deaf Slc17A8−/− mice by restoring VGLUT3 protein expression in inner hair cells, with minimal ectopic expression in the brain and none in the liver. Our findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step toward using gene therapy to restore hearing in humans.

AB - Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy showed that large-particle tracers injected into the cerebrospinal fluid reached the inner ear by dispersive transport via the cochlear aqueduct in adult mice. A single intracisternal injection of adeno-associated virus carrying solute carrier family 17, member 8 (Slc17A8), which encodes vesicular glutamate transporter-3 (VGLUT3), rescued hearing in adult deaf Slc17A8−/− mice by restoring VGLUT3 protein expression in inner hair cells, with minimal ectopic expression in the brain and none in the liver. Our findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step toward using gene therapy to restore hearing in humans.

U2 - 10.1126/scitranslmed.abq3916

DO - 10.1126/scitranslmed.abq3916

M3 - Journal article

C2 - 37379370

AN - SCOPUS:85163608254

VL - 15

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 702

M1 - eabq3916

ER -

ID: 362339478