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Application of Htra2 gene expression inhibitor in prevention of acquired sensorineural deafness

A technology for sensorineural hearing loss and gene expression, applied in the field of genetic engineering, can solve the problems of cell apoptosis, research on the ototoxicity of antibiotics that have not yet been found, etc.

Active Publication Date: 2021-07-30
EYE & ENT HOSPITAL SHANGHAI MEDICAL SCHOOL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Previous studies have shown that Omi / HtrA2 promotes the activation of caspase-3 by inhibiting the function of XIAP, leading to the occurrence of apoptosis
There is no research on regulating the Htra2 gene to antagonize the ototoxicity of aminoglycoside antibiotics

Method used

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  • Application of Htra2 gene expression inhibitor in prevention of acquired sensorineural deafness
  • Application of Htra2 gene expression inhibitor in prevention of acquired sensorineural deafness
  • Application of Htra2 gene expression inhibitor in prevention of acquired sensorineural deafness

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preventive effect of SpCas9 system on deafness caused by aminoglycoside ototoxicity.

[0026] 1. Design AAV-CRISPR / SpCas9 treatment system.

[0027] figure 1 It is the construction result diagram of the CRISPR / SpCas9 therapeutic system designed according to the mouse Htra2 gene sequence in Example 1. gRNA design diagram ( figure 1 Panel a in ) shows the targeting sequences of the three gRNAs, which are

[0028] Sp-g1: GCCTAGCGGGGATACTTATG (SEQ ID NO: 1);

[0029] Sp-g2: CTGCAGAACACGATCACATC (SEQ ID NO: 2);

[0030] Sp-g3: CGCGATGCAGAAACTCCCTA (SEQ ID NO: 3).

[0031] figure 1 Figure b in the figure is the in vitro editing efficiency results of three gRNAs; figure 1 Figure c in the figure is the proportion of three gRNAs causing In-frame and Frameshift mutations.

[0032] figure 1 Figure a in the figure also shows PAM (protospacer adjacent motif). CRISPR targeting specificity is determined by two parts, one part is the base pairing between the RNA chimera and t...

Embodiment 2

[0039] Preventive effect of SaCas9 system on deafness caused by aminoglycoside ototoxicity.

[0040] 1. Design AAV-CRISPR / SaCas9 treatment system.

[0041] image 3 It is the construction result diagram of the AAV-CRISPR / SaCas9 therapeutic system designed according to the mouse Htra2 gene sequence in Example 2. image 3 Figure a in the figure is a gRNA design diagram, which shows the targeting sequences of three gRNAs;

[0042] Sa-g1: GGAGCCCTGGAAGCCGTCGGC (SEQ ID NO: 4);

[0043] Sa-g2: AGGCACCTGGGCCGGGAGACT (SEQ ID NO: 5);

[0044] Sa-g3: GCAGATCTGACGTCTAGGACC (SEQ ID NO: 6). The sequence ends with PAM.

[0045] image 3 Figure b in the figure is the in vitro editing efficiency results of three gRNAs, and Sa-g3 with the highest editing efficiency was selected for subsequent in vivo experiments.

[0046] 2. The AAV-CRISPR / SaCas9 treatment system was introduced into the middle stage of the inner ear by microinjection in P1 of neonatal mice. Neomycin injury began at P11 ...

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Abstract

The invention discloses an application of an Htra2 gene expression inhibitor in prevention of acquired sensorineural deafness. The Htra2 gene expression inhibitor is used for preventing ototoxic deafness caused by aminoglycoside antibiotics. The invention also provides a CRISPR / Cas9 gene editing system for preventing the acquired sensorineural deafness, and the CRISPR / Cas9 gene editing system is used for targeting and knocking out the Htra2 gene. The invention proves that the AAV-CRISPR / Cas9-Htra2 gene editing system inner ear microinjection can be used for safely and effectively preventing the ototoxic deafness caused by the aminoglycoside antibiotics.

Description

technical field [0001] The invention relates to the technical field of genetic engineering, in particular to the application of an Htra2 gene expression inhibitor in the prevention of acquired sensorineural deafness. Background technique [0002] Aging, noise, infection and ototoxic drugs are the main causes of human acquired sensorineural hearing loss, but the treatment options are very limited. Adeno-associated virus (adeno-associated virus, AAV) has been used in many clinical trials and has been approved for clinical use. It has no obvious pathological effects on human cell growth, morphology or differentiation, and can infect cells in the late mitotic period. It has the advantages of high safety, weak immunogenicity, wide host range, stable physical properties, long and stable expression time, etc. A number of studies have shown that AAV is currently the preferred carrier for gene therapy of sensorineural deafness. For acquired non-hereditary sensorineural hearing loss...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K31/7088A61K9/00A61P27/16C12N15/864C12N15/55C12N15/113
CPCA61K31/7088A61K9/0046A61K9/0019A61P27/16C12N15/86C12N9/22C12N15/1137C12N2750/14143C12N2800/107C12N2310/20
Inventor 舒易来李华伟顾晰王大奇徐值娇
Owner EYE & ENT HOSPITAL SHANGHAI MEDICAL SCHOOL FUDAN UNIV
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