| Autor: |
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 |
| Zdroj: |
Science Translational Medicine; 6/28/2023, Vol. 15 Issue 702, p1-13, 13p |
| Abstrakt: |
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. Editor's summary: Although gene therapy can treat genetic hearing loss in neonatal mice, treating adult animals is harder because of the location of the cochleae and the risk of damage to inner ear structures. Here, Mathiesen and colleagues showed that the cochlear aqueduct connects the cerebrospinal fluid (CSF) and cochlear fluid in adult mice. Tracers injected into the CSF reached the mouse inner ear, and intracisternal injection of an adeno-associated virus carrying the solute carrier family 17, member 8 (Slc17A8) gene restored vesicular glutamate transporter-3 protein in the inner hair cells of the cochlea and rescued hearing in Slc17A8 knockout mice. These findings suggest that CSF administration of gene therapy through the cochlear aqueducts could be a treatment for genetic deafness in adults. —Melissa Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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