Treatment of hearing loss by inhibition of casein kinase 1
Methods for treating hearing loss that include administering an inhibitor, e.g., a small molecule inhibitor, of casein kinase 1, preferably in combination with a treatment that stimulates Atoh1 gene expression, e.g., a gamma-secretase inhibitor, an Atoh1 stimulatory compound, or a GSK-3-beta inhibitor.
1. A method of treating a subject who has or is at risk of developing hearing loss or vestibular dysfunction, the method comprising:
identifying a subject who has experienced, or is at risk for developing, hearing loss or vestibular dysfunction;
administering to the subject one or more small molecule casein kinase 1 (CK1) epsilon and/or CK1 delta inhibitors, and one or more compounds that stimulate Atoh1 gene expression;
thereby treating the hearing loss or vestibular dysfunction in the subject.
2. The method of claim 1 , wherein the subject has or is at risk for developing sensorineural hearing loss, auditory neuropathy, or both.
3. The method of claim 1 , wherein the subject has or is at risk for developing a vestibular dysfunction that results in dizziness, imbalance, or vertigo.
4. The method of claim 1 , wherein the small molecule CK1 epsilon and/or CK1 delta inhibitors and/or the one or more compounds that stimulate Atoh1 gene expression is administered systemically.
5. The method of claim 1 , wherein the small molecule CK1 epsilon and/or CK1 delta inhibitors and/or the one or more compounds that stimulate Atoh1 gene expression is administered locally to the inner ear.
6. The method of claim 1 , wherein the one or more compounds that stimulate Atoh1 gene expression comprises one or more glycogen synthase kinase 3 β (GSK3β) inhibitors.
7. The method of claim 1 , wherein the method comprises administering to the subject one or more small molecule CK1 epsilon inhibitors.
8. The method of claim 1 , wherein the one or more compounds that stimulate Atoh1 gene expression is a gamma secretase inhibitor.
9. The method of claim 1 , wherein the method comprises administering to the subject one or more small molecule CK1 delta inhibitors.
10. The method of claim 1 , wherein the one or more CK1 epsilon and/or CK1 delta inhibitors is D4476.
11. The method of claim 1 , wherein the hearing loss or vestibular dysfunction is caused by aging.
12. The method of claim 1 , wherein the hearing loss or vestibular dysfunction is caused by a genetic or congenital defect.
13. The method of claim 1 , wherein the hearing loss or vestibular dysfunction is caused by noise or trauma.
14. The method of claim 1 , wherein the hearing loss or vestibular dysfunction is caused by a chemical ototoxic insult.