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Methods of treating non-syndromic sensorineural hearing loss

A composition and carrier technology, applied in sensory diseases, gene therapy, nervous system cells, etc.

Pending Publication Date: 2021-04-09
アコーオスインコーポレイテッド
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current treatment primarily consists of hearing amplification for mild to severe hearing loss and cochlear implants for severe to profound hearing loss; need

Method used

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  • Methods of treating non-syndromic sensorineural hearing loss
  • Methods of treating non-syndromic sensorineural hearing loss
  • Methods of treating non-syndromic sensorineural hearing loss

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0297] Example 1: Construction of viral vectors

[0298]Recombinant AAV is produced by transfection using an adenovirus-free method as used by Xiao et al. J. Virol. 73(5):3994-4003,1999. A cis-plasmid with AAV ITR, a trans-plasmid with AAV Rep and Cap genes, and a helper plasmid with essential regions from the adenovirus genome were co-transfected in 293 cells at a ratio of 1:1:2. The AAV vectors used here express human sclerostin or mouse sclerostin under various two-vector strategies using the constructs described below. AAV serotypes 1, 2, 3, 4, 5, 6, 7, 8, 9, rh8, rh10, rh39, rh43, and Anc80 were each prepared to encapsulate three sets of sclerostin constructs to test (i) concatenation IL-trans-splicing strategy, (ii) heterozygous intron homologous recombination-trans-splicing strategy, and (iii) exon homologous recombination strategy, as described by Pryadkina et al., Meth.Clin.Devel. 2:15009, 2015 outlined.

Embodiment 2

[0299] Example 2: Production and purification of viral particles

[0300] Recombinant AAV-1 was generated using a triple transfection protocol and purified by two consecutive cesium chloride (CsCl) density gradients as described by Pryadkina et al., Mol. Ther. 2:15009, 2015. At the end of the second centrifugation, 11 500 μl fractions were recovered from the CsCl density gradient tubes and purified by dialysis in IX PBS. Fractions were analyzed by dot blot to determine those that contained the rAAV genome. The number of viral genomes (vg) per preparation was determined by a quantitative real-time PCR-based titration method using primers and probes corresponding to the ITR region of the AAV vector genome (Bartoli et al. Gene. Ther. 13:20-28, 2006).

Embodiment 3

[0301] Example 3: Formulation of Viral Particles

[0302] AAVs produced at a titer of 1e14 vg / mL were prepared in artificial perilymph at dilutions of 3.2e13, 1.0e13, 3.2e12, 1.0e12 vg / mL. Artificial perilymph was prepared by combining the following reagents: NaCl, 120 mM; KCl, 3.5 mM; CaCl2, 1.5 mM; glucose, 5.5 mM; HEPES, 20 mM. The artificial perilymph was titrated with NaOH to adjust its pH to 7.5 (130 mM total Na+ concentration) (Chen et al., J. Controlled Rel. 110:1-19, 2005).

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Abstract

Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of a stereocilin protein, and the use of these compositions to treat non-syndromic sensorineural hearing loss in a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to US Provisional Patent Application Serial No. 62 / 697,652, filed July 13, 2018; the entire contents of which are incorporated herein by reference. technical field [0003] The present disclosure generally relates to the use of nucleic acids to treat hearing loss in human subjects. Background technique [0004] Unlike syndromic deafness, nonsyndromic deafness is hearing loss that is not accompanied by other signs and symptoms. Seventy to eighty percent of inherited deafness cases are nonsyndromic. Although the causes of nonsyndromic deafness are complex, investigators have identified more than 30 genes (eg, Stereocilin (STRC)) that are associated with nonsyndromic deafness when altered. Current treatments primarily consist of hearing amplification for mild to severe hearing loss and cochlear implants for severe to profound hearing loss; however, there is still a long-term need. [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/85C12N5/0793C12N15/65C12N15/10C07K14/435A61K48/00A61P27/16
CPCA61K48/00A61P27/16C12N15/113C12N9/22C07K14/47C12N2310/11C12N2310/315C12N2310/321C12N2320/33C12N2750/14143C12N15/907A01K67/0275A01K2217/075A01K2227/103A01K2267/0306C12N2750/14144C12N2310/3521C12N2310/20A61K48/005C12N15/11C12N15/86C12N2830/50C12N2840/007
Inventor E.J.西蒙斯R.恩格
Owner アコーオスインコーポレイテッド
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