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Compositions and methods for prevention and treatment of hearing loss

A composition and inhibitor technology, which can be used in drug combinations, active ingredients of heterocyclic compounds, drug delivery, etc., and can solve problems such as unclearness

Pending Publication Date: 2020-09-11
TING THERAPEUTICS LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it remains unclear whether the Atoh1-mediated transition of non-sensory support cells to sensory hair cells in vivo is efficient and complete, and whether this transition bypasses the progenitor state or precisely follows the normal developmental lineage

Method used

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  • Compositions and methods for prevention and treatment of hearing loss
  • Compositions and methods for prevention and treatment of hearing loss
  • Compositions and methods for prevention and treatment of hearing loss

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Example 1: Small Molecule Inhibition of EGFR Signaling Promotes Hair Cell Regeneration

[0150] Atoh1 is a transcription factor that switches non-sensory supporting cells (SC) into hair cells (HC) in the neonatal and juvenile mammalian cochlea (Izumikawa, et al. (2005) Nature Med.11:271-6; Kelly, et al. (2012) J. Neurosci. 32:6699-710; Liu, et al. (2012) J. Neurosci. 32:6600-10). Ectopic expression of Atoh1 has been approved for clinical trials in gene therapy. However, Atoh1-induced HC conversion is inefficient (Figures 1A-1D ). In addition, inhibitors targeting proteins downstream of EGFR signaling were tested, including 50 Values ​​of various doses of WP1066 (STAT3 inhibitor), LY 294002 (PI3K inhibitor), U0126 (MEK inhibitor) and U73122 (PLC inhibitor). In addition to PLC inhibition, a similar increase in Atoh1-induced HC conversion was observed ( figure 2 ). This analysis revealed that the EGFR signaling pathway plays a novel role in the conversion of SC to HC...

Embodiment 2

[0152] Example 2: EGFR Deficiency Model of Atoh1 Overexpression Mice

[0153] Prox1-CreER (Prox1), CAG-loxp-stop-loxp-Atoh1-HA (HA), and EGFR flox / flox Crossbreeding induced mouse lines (Prox1; HA; EGFR flox / flox or PHER), where Atoh1 overexpression and EGFR loss can be specifically achieved in neonatal and juvenile SCs (Deiters cells (DC) and columnar cells (PC) below the outer HC (OHC)) after tamoxifen induction. At 3 and 6 weeks after induction, the expression of HC markers (early and late) and morphology were analyzed by immunohistochemistry, and the electrophysiological characteristics of newly generated HCs were examined with HA staining.

[0154] Similarly, Glast-CreER (Glast) has been combined with HA and EGFR flox / flox used together to generate mouse lines (Glast; HA; EGFR flox / flox or GHER). Additionally, Fgfr3-CreER; HA; EGFR was generated flox / flox or FHER mice to target adult deiter and mast cells. Cre activity will be induced at P28 adulthood and HC regener...

Embodiment 3

[0156] Example 3: Therapeutic Potential of EGFR Inhibitors in Atoh1 Overexpressing Mice

[0157]Selected EGFR inhibitors will be tested in mouse models with Atoh1 overexpression (PH, GH and FH) to determine their potential to mimic the genetic models described in Example 2 above (PHER, GHER and FHER, respectively). Six highly potent and specific EGFR inhibitors, including erlotinib, gefitinib, afatinib, NT-113, AZD3759 and dacomitinib, will be tested separately with their EC 50 Values ​​are 0.2-33 nM. These compounds have been approved by the FDA or are in clinical trials for other diseases and have relatively good absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles across species. For this analysis, Tamoxifen was used to induce Atoh1 overexpression in SC in mouse models (PH, GH and FH). Subsequently, selected compounds will be delivered by IP or TT injection. The ADMET properties of each compound in plasma, cochlear homogenate, or lymph fluid will...

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Abstract

Methods and compositions using an inhibitor of EGFR signaling for prevention or an inhibitor of EGFR signaling and a nucleic acid molecule encoding an atonal-associated factor for treatment of hearingloss are described.

Description

[0001] This patent application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 500,667, filed May 3, 2017, the entire contents of which are hereby incorporated by reference. [0002] This invention was made with government support and patents granted by the National Institutes of Health under the numbers DC006471, DC015010, DC015444, DC013879, DC013232 and CA021765 under the numbers N00014-09-V-1014, N00014-12 -V-0191, N00014-12-V-0775, and N00014-16-V-2315 were awarded by the Office of Naval Research. The government has certain rights in this invention. Background technique [0003] The ear is a complex organ consisting of a labyrinth of structures responsible for hearing and balance. Both hearing and balance lie in the ability of the structures of the inner ear to convert mechanical stimuli into impulses recognized by the brain. The sensory receptors responsible for hearing are located in the cochlea, a fluid-filled spiral tube. Inside ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K38/00A61K38/17A61K45/06A61P29/00A61P35/00
CPCA61K45/06A61P29/00A61P35/00A61K9/0019A61K38/1709A61K38/30A61K31/4155A61K31/4706A61K31/4709A61K31/506A61K31/517A61K31/519C07K14/4702C07K14/4703A01K67/0275A01K2217/052A01K2217/15A01K2217/206A01K2227/105A01K2267/03A61P27/16A61K31/18A61K31/422A61K31/44A61K31/5377A61K31/58A61K31/713A61K39/3955
Inventor J·左T·泰兹F·郑T·山下Z·卡拉德J·闵T·S·陈
Owner TING THERAPEUTICS LLC
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