Reversal of an existing hearing loss by gene activation in Spns2 mutant mice

TY - JOUR

T1 - Reversal of an existing hearing loss by gene activation in Spns2 mutant mice

AU - Martelletti, Elisa

AU - Ingham, Neil J

AU - Steel, Karen P

PY - 2023/8/22

Y1 - 2023/8/22

N2 - Hearing loss is highly heterogeneous, but one common form involves a failure to maintain the local ionic environment of the sensory hair cells reflected in a reduced endocochlear potential. We used a genetic approach to ask whether this type of pathology can be reversed, using the Spns2tm1a mouse mutant known to show this defect. By activating Spns2 gene transcription at different ages after the onset of hearing loss, we found that an existing auditory impairment can be reversed to give close to normal thresholds for an auditory brainstem response (ABR), at least at low to mid stimulus frequencies. Delaying the activation of Spns2 led to less effective recovery of ABR thresholds, suggesting that there is a critical period for intervention. Early activation of Spns2 not only led to improvement in auditory function but also to protection of sensory hair cells from secondary degeneration. The genetic approach we have used to establish that this type of hearing loss is in principle reversible could be extended to many other diseases using available mouse resources.

AB - Hearing loss is highly heterogeneous, but one common form involves a failure to maintain the local ionic environment of the sensory hair cells reflected in a reduced endocochlear potential. We used a genetic approach to ask whether this type of pathology can be reversed, using the Spns2tm1a mouse mutant known to show this defect. By activating Spns2 gene transcription at different ages after the onset of hearing loss, we found that an existing auditory impairment can be reversed to give close to normal thresholds for an auditory brainstem response (ABR), at least at low to mid stimulus frequencies. Delaying the activation of Spns2 led to less effective recovery of ABR thresholds, suggesting that there is a critical period for intervention. Early activation of Spns2 not only led to improvement in auditory function but also to protection of sensory hair cells from secondary degeneration. The genetic approach we have used to establish that this type of hearing loss is in principle reversible could be extended to many other diseases using available mouse resources.

KW - Animals

KW - Mice

KW - Hearing Loss/genetics

KW - Anion Transport Proteins/genetics

KW - Genetic Therapy

KW - Transcriptional Activation

KW - Cochlear Microphonic Potentials

KW - Hair Cells, Auditory/pathology

U2 - 10.1073/pnas.2307355120

DO - 10.1073/pnas.2307355120

M3 - Article

C2 - 37552762

SN - 0027-8424

VL - 120

SP - e2307355120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 34

ER -