Increasing ATOH1 life to drive sensorineural hair cell differentiation
The present disclosure provides compositions and methods for treating subjects at risk for or with sensorineural hearing loss by modulating the rate of Atoh1 protein degradation to increase levels of Atoh1 protein.
1. A long-lived human Atoh1 variant polypeptide comprising a mutation at the amino acid position corresponding to amino acid 328 of SEQ ID NO: 1.
2. The long-lived human Atoh1 variant polypeptide of claim 1 , which is at least 95% identical to SEQ ID NO: 1.
3. The long-lived human Atoh1 variant polypeptide of claim 1 , wherein the amino acid at the position corresponding to amino acid 328 of SEQ ID NO: 1 is not serine.
4. The long-lived human Atoh1 variant polypeptide of claim 1 , comprising SEQ ID NO: 1 with a mutation of S328A.
5. The long-lived human Atoh1 variant polypeptide of claim 1 , further comprising a mutation at the amino acid positions corresponding to amino acids 331, and/or 334 of SEQ ID NO: 1.
6. The long-lived human Atoh1 variant polypeptide of claim 5 , wherein one or both of the amino acids at the positions corresponding to amino acids 331 and/or 334 of SEQ ID NO: 1 is not serine.
7. The long-lived human Atoh1 variant polypeptide of claim 1 , comprising SEQ ID NO: 1 with mutations selected from the group consisting of S328A/S331A, S328A/S334A, and S328A/S331A/S334A.
8. A long-lived human Atoh1 variant polypeptide comprising SEQ ID NO: 1 with a mutation of S334A.
9. The long-lived human Atoh1 variant polypeptide of claim 8 , further comprising a mutation at the amino acid position corresponding to amino acid 331 of SEQ ID NO: 1.
10. The long-lived human Atoh1 variant polypeptide of claim 9 , wherein the amino acid at the position corresponding to amino acid 331 of SEQ ID NO: 1 is not serine.
11. The long-lived human Atoh1 variant polypeptide of claim 9 , comprising SEQ ID NO: 1 with mutations of S331A/S334A.