Methods and compositions for regenerating hair cells and/or supporting cells

a technology of supporting cells and hair cells, which is applied in the direction of drug compositions, dsdna viruses, peptide/protein ingredients, etc., can solve the problems of reducing the existing population of supporting cells, unable to replace lost or damaged cells, and impairing inner ear function, so as to promote cell cycle reentry and proliferation, increase c-myc activity, or both c-myc, the effect of restoring or improving hearing and/or vestib

Inactive Publication Date: 2015-07-30
MASSACHUSETTS EYE & EAR INFARY
View PDF3 Cites 15 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The invention is based, in part, upon the discovery that increasing c-myc activity, Notch activity, or both c-myc and Notch activity in an ear cell, for example, a cell of an inner ear, promotes cell cycle reentry and proliferation of the cell. When the cell is, for example, a hair cell or a supporting cell, it is contemplated that proliferation and subsequent differentiation of the cell into hair and / or supporting cells can restore or improve hearing and / or vestibular function.

Problems solved by technology

The human inner ear contains only about 15,000 hair cells per cochlea at birth, and, although these cells can be lost as a result of various genetic or environmental factors (e.g., noise exposure, ototoxic drug toxicity, viral infection, aging, and genetic defects), the lost or damaged cells cannot be replaced.
One limitation to this approach, however, is that transdifferentiation of supporting cells to hair cells diminishes the existing population of supporting cells, which can impair inner ear function.
In addition, overexpression of Atoh1 in aged inner ear or flat epithelium, which lacks supporting cells, is not sufficient to induce hair cells.
Furthermore, it is not clear if all types of supporting cells can be transdifferentiated into hair cells upon Atoh1 overexpression.
However similar manipulations in the adult inner ear have not induced cell cycle reentry.
For example, mutations in Myosin VIIa (Myo7a) cause hair cell stereocilia abnormalities that lead to permanent deafness.
However most of these defects occur during embryonic development.
By birth, affected hair cells and supporting cells already have died or are severely degenerated, making intervention difficult.
Inner ear non-sensory cells can be damaged by factors such as noise and aging, which contribute to hearing loss.
These cell types, like many of those in the inner ear, lack the capacity to regenerate spontaneously after damage.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Methods and compositions for regenerating hair cells and/or supporting cells
  • Methods and compositions for regenerating hair cells and/or supporting cells
  • Methods and compositions for regenerating hair cells and/or supporting cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

In Vivo Induction of Cell Cycle Reentry in Adult Cochlear Cells Via C-Myc and Notch

[0203]This example demonstrates that providing c-myc and Notch to cells of the inner ear of an adult animal can induce cell cycle reentry and cell proliferation among differentiated cochlear hair and supporting cells.

[0204]Adult mice aged between 1 and 15 months were used to investigate the potential for c-myc and Notch to induce cell cycle reentry, proliferation, differentiation, and survival among cochlear hair and supporting cells. In separate experiments, the mice used were either wild type (WT) background mice or mice harboring a LoxP-flanked NICD cassette (NICDflox / flox) susceptible to Cre-mediated recombination resulting in activation of NICD expression. The NICD cassette encoded (from 5′ to 3′) an intracellular fragment of mouse Notch1 (amino acids 1749-2293, lacking the C-terminal PEST domain, see Murthaugh et al. (2003) PROC. NATL. ACAD. SCI. U.S.A. 100(25):14920-14925.) Mice were anaestheti...

example 2

In Vivo Induction of Cell Cycle Reentry in Cochlear Cells of Aced Mice via C-Myc and Notch

[0209]The following example demonstrates that providing c-myc and Notch to cells of the inner ear can also induce cell cycle reentry and cell proliferation among differentiated cochlear hair and supporting cells in aged animal subjects.

[0210]Ad-Myc and Ad-Cre-GFP were injected once into 17-month old NICDflox / flox mouse cochlear scala media via cochleostomy and the animals were harvested 15 days later. 0.3 μl of a mixture of an equal amount of Ad-Cre-GFP and Ad-Myc with a titer of 2×1012 was injected. BrdU (50 μg / g body weight) was also injected once per day for 15 days to label cycling cells. The same protocol was used as a control, in which only Ad-Cre was injected into the cochlea. Cochlear tissue harvested following BrdU and virus injection demonstrated that cells of the aged mouse cochlea underwent cell re-entry, as evidenced by the presence of double-labeled hair (BrdU+ / Myo7a+) and suppor...

example 3

Induction of Cell Cycle Reentry in Cultured Adult Cells Harvested from Inner Ear Tissue of Various Mammals

[0212]The following example demonstrates that exposure to increased c-myc and Notch activity supports cell cycle reentry and proliferation of adult mouse, monkey and human hair and supporting cells of the inner ear.

[0213]In order to investigate whether increased c-myc and Notch activity induce cell cycle reentry and proliferation in human cells, adult human cochlear and utricular tissue was collected. Samples were derived from surgeries during which such tissue was discarded. Cells were cultured in high glucose Dulbecco's modified Eagle's medium and F 12 medium supplemented with N2 and B27 (Media and supplements were from Invitrogen / GIBCO / BRL, Carlsbad, Calif.), and 1% FBS was added.

[0214]A working viral titer of 108 was used for 5 mL of culture. Cultures of harvested tissue and transduced cultured cells were contacted with a mixture of Ad-Myc and Ad-NICD, to elevate cellular le...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

Provided are methods and compositions for inducing cells of the inner ear (for example, cochlear and utricular hair cells) to reenter to cell cycle and to proliferate. More particularly, the invention relates to the use of agents that increase c-myc activity and/or Notch activity for inducing cell cycle reentry and proliferation of cochlear or utricular hair cells and/or cochlear or utricular supporting cells. The methods and compositions can be used to promote the proliferation of hair cells and/or supporting cells to treat a subject at risk of or affected with, hearing loss or a subject at risk of or affected with vestibular dysfunction.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims priority to and the benefit of U.S. Provisional Patent Application No. 61 / 698,246, which was filed on Sep. 7, 2012, the entire contents of which are incorporated by reference herein.FIELD OF THE INVENTION[0002]The field of the invention relates generally to methods and compositions for inducing inner ear cells to reenter the cell cycle and to proliferate. More particularly, the invention relates to increasing c-myc and / or Notch activity within cells to induce cell cycle reentry and proliferation of hair cells and / or supporting cells of the inner ear.BACKGROUND OF THE INVENTION[0003]One of the most common types of hearing loss is sensorineural deafness that is caused by the loss of hair cells or hair cell function. Hair cells are sensory cells in the cochlea responsible for transduction of sound into an electrical signal. The human inner ear contains only about 15,000 hair cells per cochlea at birth, and, although th...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17C12N5/0793
CPCA61K38/177A61K38/1709A61K48/00C12N2501/42C12N2501/606C12N5/062A61K38/16A61K31/65A61K48/005C12N2710/10341A61K35/30A61P25/28A61P27/16A61P43/00
Inventor CHEN, ZHENG-YI
Owner MASSACHUSETTS EYE & EAR INFARY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap