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

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...

AI Technical Summary

Benefits of technology

The invention is based on the discovery that increasing c-myc or Notch activity in inner ear cells promotes cell cycle reentry and proliferation of the cells. This can lead to the formation of new hair cells or supporting cells which can improve hearing or solving issues related to balance. The invention also includes a method for reducing hearing or vestibular function loss by increasing c-myc or Notch activity and inducing cell proliferation, followed by decreasing the activity and allowing the cells to differentiate. The method can be performed in vivo or ex vivo, and can be used to develop therapies for inner ear disorders.

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.

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