Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice
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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
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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
N1 - Publisher Copyright: © 2023 American Association for the Advancement of Science. All rights reserved.
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