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Composition for promoting hair cell regeneration and hearing recovery and application thereof

A composition and hair cell technology, applied in the field of biomedicine, can solve problems such as difficulty in achieving hair cell differentiation, maturation and survival, low efficiency of hair cell transdifferentiation, hair cell death, etc., so as to promote the reprogramming and maturation of hair cells. , Efficient hair cell differentiation, the effect of promoting hair cell regeneration and maturation

Active Publication Date: 2020-09-11
NANJING UNIV
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0005] Aiming at the problem of further promoting the recovery of auditory function by expressing Atoh1, knocking down Sox2 or inhibiting Notch in the prior art, it is easy to cause the immaturity of induced hair cells and eventually die, and the efficiency of promoting hair cell transdifferentiation is still very low. , it is difficult to achieve high-efficiency hair cell differentiation, maturation and survival. The present invention explores and reveals a new signaling axis, that is, it is found that the series of VEGFR, TGFB1 and ERG is an inhibitory signal for hair cell regeneration. By combining the EGFR-TGFB1-ERG Combining any one of the inhibitors in the cascade pathway with a Wnt agonist to prepare a composition to promote hair cell regeneration and maturation, and to achieve efficient hair cell differentiation, maturation and survival

Method used

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  • Composition for promoting hair cell regeneration and hearing recovery and application thereof
  • Composition for promoting hair cell regeneration and hearing recovery and application thereof
  • Composition for promoting hair cell regeneration and hearing recovery and application thereof

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Embodiment

[0098] Experimental materials: Mouse strains include:

[0099] 1. Lgr5-EGFP-IRES-CreER (#008875) (Barker et al., 2007);

[0100] 2. Plp1-CreER (#005975) (Doerflinger et al., 2003);

[0101] 3. Sox2-CreER (#017593) (Arnold et al., 2011) and Rosa26-ACTB-mTmG (#007676) (Muzumdar et al., 2007) mice were obtained from Jackson Laboratory.

[0102] 4. Rosa26-CAG-STOP-Cas9-tdTomato (Rosa26-tdTomato) mice were obtained from Gempharmatech Inc in China.

[0103] 5. Pou4f3-EGFP-IRES-CreER (Pou4f3(EGFP / +)) knock-in mice were obtained using CRISPR-Cas9 gene editing technology: two cutting strategies were used to insert the EGFP-IRES-CreER cassette into the Pou4f3 locus. Two Pou4f3 sgRNAs: 5'-AGTACGGGGTGCATGCCGAA-3' and 5'-TGAACGGATGATTCTTGCCG-3' were cloned into PX330 plasmid and generated by in vitro transcription (T7 as promoter) using MEGA shortscript kit (Ambion, Am1354, USA) sgRNA. To keep the Pou4f3 regulatory elements intact, an EGFP-IRES-CreER cassette was integrated at the firs...

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Abstract

The invention belongs to the field of biological medicines, and discloses a composition for promoting hair cell regeneration and hearing recovery and an application thereof. The composition comprisesa Wnt agonist and one or more of the following reagents: (a) a VEGFR inhibitor; (b) a Tgfbr inhibitor; and (c) an ERG inhibitor. The VEGFR inhibitor comprises regorafenib, apatinib mesylate, cabozantinib, pazopanib hydrochloride and medicinal salts or derivatives of the regorafenib, the apatinib mesylate, the cabozantinib and the pazopanib hydrochloride. An organoid platform verifies that after any inhibitor in a signal axis of EGFR-TGFB1-ERG is combined with the Wnt agonist to prepare the composition, efficient hair cell differentiation, maturation and survival can be realized, and the composition has important value for hearing recovery.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a composition for promoting hair cell regeneration and hearing recovery and its application. Background technique [0002] Hearing loss is the most common sensory impairment, affecting more than 320 million people worldwide. The degeneration of cochlear sensory hair cells is the main cause of sensorineural hearing loss. Degeneration of cochlear hair cells can be caused by genetic defects, noise exposure, aging, ototoxic drugs, and other environmental damage. After injury from ototoxic drugs or noise, birds and amphibians can restore hearing function by regenerating new hair cells from surrounding support cells. However, in the postnatal mammalian cochlea, despite the presence of multiple cochlear supporting cells, these cells are postmitotic and unable to regenerate hair cells. Thus, damage to cochlear hair cells in mammals can lead to permanent hearing loss. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/404A61K31/44A61K31/4439A61K31/444A61K31/47A61P27/16C12N5/071
CPCA61K45/06A61K31/47A61K31/4439A61K31/404A61K31/44A61K31/444A61P27/16C12N5/062C12N2501/415C12N2501/165C12N2501/15C12N2501/60A61K2300/00
Inventor 万国强柳晴
Owner NANJING UNIV
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