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Generation of inner ear cells / Massachusetts Eye & Ear Infirmary




Title: Generation of inner ear cells.
Abstract: Methods for generating cells of the inner ear, e.g., hair cells and supporting cells, from stem cells, e.g., mesenchymal stem cells, are provided, as well as compositions including the inner ear cells. Methods for the therapeutic use of the inner ear cells for the treatment of hearing loss are also described. ...


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USPTO Applicaton #: #20090098093
Inventors: Albert Edge


The Patent Description & Claims data below is from USPTO Patent Application 20090098093, Generation of inner ear cells.

CLAIM OF PRIORITY

This application is continuation of International Application No. PCT/US2007/084654, filed on Nov. 14, 2007, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/859,041, filed on Nov. 15, 2006; the entire contents of the foregoing applications are hereby incorporated by reference.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant No. F33 DC006789, RO1 DC007174, and P30 DC05209 from the National Institute on Deafness and other Communicative Disorders (NIDCD) of the National Institutes of Health. The Government has certain rights in the invention.

TECHNICAL FIELD

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This invention relates to methods using bone marrow mesenchymal stem cells to regenerate inner ear cells, e.g., hair cells and supporting cells, to treat inner ear damage.

BACKGROUND

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A source of sensory cells and neurons for regeneration of inner ear cells would provide a valuable tool for clinical application because neurons and hair cells could be employed in cell replacement therapy for hearing loss. Recent work has shown that hair cells and neurons can be differentiated from endogenous stem cells of the inner ear (Li et al., Nat Med 9, 1293-1299 (2003); Rask-Andersen et al., Hear Res 203, 180-191 (2005)) and other work has shown that endogenous cells of the sensory epithelium can be converted to hair cells when the proneural transcription factor, Atoh1, is expressed exogenously (Izumikawa et al., Nat Med 11, 271-276 (2005); Zheng and Gao, Nat Neurosci 3, 580-586 (2000)) and yet the endogenous stem cells of the inner ear do not spontaneously generate hair cells. Injection of whole bone marrow to reconstitute a lethally irradiated mouse resulted in engraftment of these cells in areas occupied by inner ear mesenchymal cells and fibrocytes but did not yield hair cells (Lang et al., J Comp Neurol 496, 187-201 (2006)).

SUMMARY

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The present invention is based, at least in part, on the discovery of methods that can be used to induce stem cells to differentiate into hair cells and supporting cells. Thus, described herein are methods for providing populations of hair cells and/or supporting cells, compositions comprising said cells, and methods of use thereof, e.g., for the treatment of subjects who have or are at risk of developing a hearing loss.

In one aspect, the invention provides methods for providing populations of hair cells and/or supporting cells. The methods include:

obtaining a population of stem cells with neurogenic potential;

culturing the stem cells under conditions sufficient to induce the differentiation of at least some of the stem cells into inner ear progenitor cells, and doing one (or more) of the following: (i) inducing the expression of Atoh1 in the inner ear progenitor cells, in an amount and for a time sufficient to induce at least some of the inner ear progenitor cells to differentiate into hair cells; (ii) contacting the inner ear progenitor cells with an inhibitor of Notch signalling (e.g., a gamma-secretase inhibitor or inhibitory nucleic acid), in an amount and for a time sufficient to induce at least some of the inner ear progenitor cells to differentiate into hair cells; or (iii) culturing the inner ear progenitor cells in the presence of chick otocyst cells for a time and under conditions sufficient for at least some of the

inner ear progenitor cells to differentiate into hair cells, thereby providing populations of hair cells and/or supporting cells.

In some embodiments, the methods include isolating the inner ear progenitor cells, hair cells, and/or supporting cells, e.g., to provide a purified population thereof.

In some embodiments, the inner ear progenitor cells express nestin, sox2, musashi, Brn3C, Pax2, and Atoh1.

In some embodiments, the hair cells express one or more genes selected from the group consisting of Atoh1, jagged 2, Bm3c, p27Kip, Ngn1, NeuroD, myosin VIIa and espin. In some embodiments, the hair cells express jagged 2, Brn3c, myosin VIIa and espin. In some embodiments, the hair cells express F-actin in a V pattern on the apical surface of the cells.

In some embodiments, the supporting cells express one or more of claudin14, connexin 26, p75Trk, Notch 1, and S100A.

In some embodiments, the methods further include transplanting the hair cells or supporting cells into a subject in need thereof, e.g., into or near the sensory epithelium of the subject. In some embodiments, the population of stem cells is obtained from a subject in need of the transplant.

Also described herein are isolated populations of hair cells, supporting cells, and inner ear progenitor cells obtained by a method described herein.

In another aspect, the invention features methods for treating a subject who has or is at risk for developing a disorder, e.g., a hearing disorder or vestibular disorder, wherein the disorder is treatable with a transplant of hair cells and/or supporting cells, the method comprising transplanting cells obtained by a method described herein into the cochlea of the subject, thereby treating the subject. In these embodiments, it is preferable if the population of stem cells was obtained from the subject in need of the transplant.

In some embodiments, inducing the expression of Atoh1 in the cells comprises inducing the expression of exogenous Atoh1 in the cells, e.g., by transducing the cells with a vector encoding a Atoh1 polypeptide, e.g., a plasmid vector or a viral vector, e.g., an adenovirus, lentivirus, or retrovirus.

In some embodiments, inducing the expression of exogenous Atoh1 in the stem cells comprises increasing expression of endogenous Atoh1, e.g., by increasing activity of the Atoh1 promoter or by replacing the endogenous Atoh1 promoter with a more highly active promoter.

In some embodiments, culturing the stem cells in the presence of chick otocyst cells for a time and under conditions sufficient for at least some of the stem cells to differentiate into hair cells comprises culturing the stem cells in medium comprising IGF, EGF, and FGF.




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stats Patent Info
Application #
US 20090098093 A1
Publish Date
04/16/2009
Document #
File Date
12/31/1969
USPTO Class
Other USPTO Classes
International Class
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Drawings
0


Hair Cells Hearing Loss Inner Ear

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20090416|20090098093|generation of inner ear cells|Methods for generating cells of the inner ear, e.g., hair cells and supporting cells, from stem cells, e.g., mesenchymal stem cells, are provided, as well as compositions including the inner ear cells. Methods for the therapeutic use of the inner ear cells for the treatment of hearing loss are also |Massachusetts-Eye-&-Ear-Infirmary
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