IP Library › Granted Patent US 12,618,070
Granted Patent B2
US 12,618,070 · App. 17/686,734 · Granted May 5, 2026

Increasing Atoh1 life to drive sensorineural hair cell differentiation

Inventors: Albert Edge (Brookline, MA); Yen-Fu Cheng (Boston, MA); Judith Kempfle (Brookline, MA); Dunia Abdul-Aziz (Boston, MA)
Assignee: Massachusetts Eye and Ear Infirmary
C12N15/1137A61K9/0046A61K31/407A61K31/69A61K31/7105A61K31/713A61K38/05A61K38/06A61K38/07A61K38/12A61K38/15A61K38/1709A61K45/06A61K48/0075C07K14/47C12N15/113C12Y603/02019A61K38/00C12N2310/14
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Quick Facts
Patent No.
US 12,618,070
App. No.
17/686,734
Granted
May 5, 2026
Kind
B2
Abstract

The present disclosure provides compositions and methods for treating subjects at risk for or with sensorineural hearing loss by modulating the rate of Atoh1 protein degradation to increase levels of Atoh1 protein.

Claims (13)

1 . An expression vector comprising a polynucleotide encoding a human Atoh1 variant polypeptide, wherein the human Atoh1 variant polypeptide is a long-lived human Atoh1 variant polypeptide comprising a mutation at the amino acid position corresponding to amino acid 334 of SEQ ID NO: 1, and wherein the long-lived human Atoh1 variant polypeptide is at least 95% identical to SEQ ID NO: 1.

2 . The expression vector of claim 1 , wherein the amino acid at the position corresponding to amino acid 334 of SEQ ID NO: 1 is not serine.

3 . The expression vector of claim 1 , wherein the long-lived human Atoh1 variant polypeptide comprises SEQ ID NO: 1 with a mutation of S334A.

4 . The expression vector of claim 1 , wherein the long-lived human Atoh1 variant polypeptide further comprises a mutation at the amino acid position corresponding to amino acid 331 of SEQ ID NO: 1.

5 . The expression vector of claim 4 , wherein the amino acid at the position corresponding to amino acid 331 of SEQ ID NO: 1 is not serine.

6 . The expression vector of claim 1 , wherein the long-lived human Atoh1 variant polypeptide comprises SEQ ID NO: 1 with mutations S331A/S334A.

7 . The expression vector of claim 1 , which is a viral vector.

8 . The expression vector of claim 7 , wherein the viral vector is selected from the group consisting of recombinant retrovirus, adenovirus, adeno-associated virus, and lentivirus.

9 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a human Atoh1 variant polypeptide, wherein the human Atoh 1 variant polypeptide is a long-lived human Atoh1 variant polypeptide comprising a mutation at the amino acid position corresponding to amino acid position 334 of SEQ ID NO: 1, and wherein the long-lived human Atoh1 variant polypeptide is at least 95% identical to SEQ ID NO: 1.

10 . The isolated nucleic acid molecule of claim 9 , wherein the long-lived human Atoh1 variant polypeptide comprises SEQ ID NO: 1 with a mutation of S334A.

11 . The isolated nucleic acid molecule of claim 9 , wherein the long-lived human Atoh1 variant polypeptide comprises SEQ ID NO: 1 with mutations S331A/S334A.

12 . The isolated nucleic acid molecule of claim 9 , wherein the nucleotide sequence further encodes a 5′ untranslated region.

13 . The isolated nucleic acid molecule of claim 9 , which is at least 95% identical to SEQ ID NO: 2.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 2, 2026
From: EDGE, ALBERT; CHENG, YEN-FU; KEMPFLE, JUDITH; ABDUL-AZIZ, DUNIA
To: MASSACHUSETTS EYE AND EAR INFIRMARY
Reel/Frame 074253/0988 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2022
From: EDGE, ALBERT; CHENG, YEN-FU; KEMPFLE, JUDITH; ABDUL-AZIZ, DUNIA
To: MASSACHUSETTS EYE AND EAR INFIRMARY
Reel/Frame 059853/0831 →
Continuity (5)
Division 16358579 · Mar 19, 2019
Continuation 15502113
Provisional Application 62034459 · Aug 7, 2014
Provisional Application 62034040 · Aug 6, 2014
Related Publication 20220259602A1 · Aug 18, 2022
References Cited (400)
US 4522811A · Eppstein et al. · 1985 [cited by applicant]
US D309535S · Wilson · 1990 [cited by applicant]
US D360535S · Sjoberg · 1995 [cited by applicant]
US 5695995A · Weintraub · 1997 [cited by examiner]
US D447031S · Oh · 2001 [cited by applicant]
US 6417185B1 · Goff et al. · 2002 [cited by applicant]
US 6489344B1 · Nuss et al. · 2002 [cited by applicant]
US 6608063B2 · Nuss et al. · 2003 [cited by applicant]
US 6756511B2 · Castro Pineiro et al. · 2004 [cited by applicant]
US 6890956B2 · Churcher et al. · 2005 [cited by applicant]
US 6984626B2 · Nadin et al. · 2006 [cited by applicant]
US 7049296B2 · Castro Pineiro et al. · 2006 [cited by applicant]
US 7101895B2 · Churcher et al. · 2006 [cited by applicant]
US 7138400B2 · Collins et al. · 2006 [cited by applicant]
US 7144910B2 · Madin et al. · 2006 [cited by applicant]
US 7183303B2 · Castro Pineiro et al. · 2007 [cited by applicant]
US 7206639B2 · Jacobsen et al. · 2007 [cited by applicant]
US 7399633B2 · Bernstein et al. · 2008 [cited by applicant]
US D646625S · Youn · 2011 [cited by applicant]
US 8188069B2 · Miller et al. · 2012 [cited by applicant]
US 8518944B2 · Subramanyam et al. · 2013 [cited by applicant]
US 8617810B2 · Heller et al. · 2013 [cited by applicant]
US 8673634B2 · Li et al. · 2014 [cited by applicant]
US 10406163B2 · Edge et al. · 2019 [cited by applicant]
US 10603295B2 · Edge et al. · 2020 [cited by applicant]
US 10925872B2 · Lorrain et al. · 2021 [cited by applicant]
US 20030114381A1 · Cotanche et al. · 2003 [cited by applicant]
US 20040029862A1 · Belanger et al. · 2004 [cited by applicant]
US 20040049038A1 · Collins et al. · 2004 [cited by applicant]
US 20040186147A1 · Hannam et al. · 2004 [cited by applicant]
US 20050019801A1 · Rubin et al. · 2005 [cited by applicant]
US 20050119293A1 · Collins et al. · 2005 [cited by applicant]
US 20050143369A1 · Castro Pineiro et al. · 2005 [cited by applicant]
US 20050182109A1 · Collins et al. · 2005 [cited by applicant]
US 20050182111A1 · Pineiro et al. · 2005 [cited by applicant]
US 20050215602A1 · Campbell et al. · 2005 [cited by applicant]
US 20050287127A1 · Li et al. · 2005 [cited by applicant]
US 20060030837A1 · McKenna et al. · 2006 [cited by applicant]
US 20070093878A1 · Edge et al. · 2007 [cited by applicant]
US 20080146617A1 · Aud et al. · 2008 [cited by applicant]
US 20080267929A1 · Li et al. · 2008 [cited by applicant]
US 20090098093A1 · Edge · 2009 [cited by applicant]
US 20090099237A1 · Aud et al. · 2009 [cited by applicant]
US 20090124568A1 · Heller et al. · 2009 [cited by applicant]
US 20090232780A1 · Edge et al. · 2009 [cited by applicant]
US 20090297533A1 · Lichter et al. · 2009 [cited by applicant]
US 20090306225A1 · Lichter et al. · 2009 [cited by applicant]
US 20100273864A1 · Lichter et al. · 2010 [cited by applicant]
US 20110020232A1 · Eberhart et al. · 2011 [cited by applicant]
US 20110033480A1 · Sarkar et al. · 2011 [cited by applicant]
US 20110305674A1 · Edge et al. · 2011 [cited by applicant]
US 20110319377A1 · Lichter et al. · 2011 [cited by applicant]
US 20130085112A1 · Collard et al. · 2013 [cited by applicant]
US 20130210145A1 · Edge · 2013 [cited by applicant]
US 20130225543A1 · Jones et al. · 2013 [cited by applicant]
US 20140044763A1 · Kustov et al. · 2014 [cited by applicant]
US 20150030568A1 · Li et al. · 2015 [cited by applicant]
US 20150209406A1 · Chen · 2015 [cited by applicant]
US 20170349884A1 · Karp et al. · 2017 [cited by applicant]
US 20180148456A1 · Clay et al. · 2018 [cited by applicant]
US 20190010449A1 · Edge et al. · 2019 [cited by applicant]
US 20190203210A1 · Edge et al. · 2019 [cited by applicant]
US 20190247381A1 · Edge et al. · 2019 [cited by applicant]
US 20200255800A1 · Edge · 2020 [cited by applicant]
US 20210290686A1 · Edge et al. · 2021 [cited by applicant]
US 20210299138A1 · Edge et al. · 2021 [cited by applicant]
US 20220008433A1 · Edge et al. · 2022 [cited by applicant]
CN 1441841 · 2003 [cited by applicant]
GB 2459910 · 2009 [cited by applicant]
JP 2006117536 · 2006 [cited by applicant]
JP 2006520386 · 2006 [cited by applicant]
JP 2007503816 · 2007 [cited by applicant]
JP 2007526248 · 2007 [cited by applicant]
JP 2011518195 · 2011 [cited by applicant]
JP 2012509899 · 2012 [cited by applicant]
WO WO1998028268 · 1998 [cited by applicant]
WO WO2000053632 · 2000 [cited by applicant]
WO WO2000059939 · 2000 [cited by applicant]
WO WO2001070677 · 2001 [cited by applicant]
WO WO2002049038 · 2002 [cited by applicant]
WO WO2003093251 · 2003 [cited by applicant]
WO WO2003093252 · 2003 [cited by applicant]
WO WO2003093253 · 2003 [cited by applicant]
WO WO2003093264 · 2003 [cited by applicant]
WO WO2004039370 · 2004 [cited by applicant]
WO WO2004039800 · 2004 [cited by applicant]
WO WO2005014553 · 2005 [cited by applicant]
WO WO2005030731 · 2005 [cited by applicant]
WO WO2006026570 · 2006 [cited by applicant]
WO WO2007075911 · 2007 [cited by applicant]
WO WO2008076556 · 2008 [cited by applicant]
WO WO2008076556A2 · 2008 [cited by examiner]
WO WO2009087130 · 2009 [cited by applicant]
WO WO2009132050 · 2009 [cited by applicant]
WO WO2010060088 · 2010 [cited by applicant]
WO WO2012005805 · 2012 [cited by applicant]
WO WO2014145205 · 2014 [cited by applicant]
WO WO2014159356 · 2014 [cited by applicant]
WO WO2015168149 · 2015 [cited by applicant]
WO WO2016022776 · 2016 [cited by applicant]
WO WO2016037016 · 2016 [cited by applicant]
WO WO2017151907 · 2017 [cited by applicant]
WO WO2018111926 · 2018 [cited by applicant]
Forget et al (Dev Cell 29: 649-661, Jun. 23, 2014) (Year: 2014). [cited by examiner]
MSCV retrovirus system, on Mar. 14, 2025, 2 pages (Year: 2025). [cited by examiner]
Pickering et al (Sem Cell Dev Biol 16: 39-47, 2005) (Year: 2005). [cited by examiner]
Office Action in Japanese Appln. No. 2022-069599, dated Jun. 6, 2023, 3 pages (with English translation). [cited by applicant]
Abbott et al., “Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains,” Molecular and Cellular Biology, 2007, 27:6012-6025. [cited by applicant]
Adam et al., “Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with [cited by applicant]
Adamo et al., “LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells,” Nat Cell Biol, Jun. 2011, 13(6):652-659, 20 pages. [cited by applicant]
Adhikary et al., The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation, Cell, 2005, 123 :409-421. [cited by applicant]
Adler and Raphael, “New hair cells arise from supporting cell conversion in the acoustically damaged chick inner ear,” Neuroscience Letters, Feb. 1996, 205: 17-20. [cited by applicant]
Ahmed and Streit, “LSD1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity,” Development, 2018, 145(4):dev160325, 9 pages. [cited by applicant]
Aletsee et al., “The disintegrin Kistrin inhibits neurite extension from spiral ganglion explants cultured on laminin,” Audiol. Neurootol., 6:57-65 (2001). [cited by applicant]
Armstrong et al, “Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells,” Neuroscience, Sep. 2001, 106(1):201-216. [cited by applicant]
Artavanis-Tsakonas et al., “Notch Signaling,” Sci., 1995, 268:225-232. [cited by applicant]
Azuara et al., “Chromatin signatures of pluripotent cell lines,” Nat Cell Biol, May 2006, 8(5):532-538, 11 pages. [cited by applicant]
Ballas et al., “Regulation of neuronal traits by a novel transcriptional complex,” Neuron, Aug. 2001, 31(3):353-365. [cited by applicant]
Barker et al, “A Role for Complement in the Rejection of Porcine Ventral Mesencephalic Xenografts in a Rat Model of Parkinson's Disease,” The Journal of Neuroscience, May 2000, 20(9):3415-3424. [cited by applicant]
Barker et al., “Identification of stem cells in small intestine and colon by marker gene Lgf5,” Nature, 2007, 449: 1003-1007. [cited by applicant]
Barker, “Wnt Signaling: Volume 1: Pathway Methods and Mammalian Models,” in Methods in Molecular Biology, Nov. 2008, 5-15. [cited by applicant]
Bartolami et al., “Appearance and Distribution of the 275 kD Hair-Cell Antigen During Development of the Avian Inner Ear,” J. Comp. Neurol., 314:777-788 (1991). [cited by applicant]
Basi et al., “Amyloid precursor protein selective gamma-secretase inhibitors for treatment Amyloid precursor protein selective gamma-secretase of Alzheimer's disease,” Alzheimer's Research & Therapy, 2:36 (2010) pp. 1-2… [cited by applicant]
Batts et al., “Notch signaling and Hes labeling in the normal and drug-damaged organ of Corti,” Hear Res., 249:15-22 (Mar. 2009). [cited by applicant]
Becvarovski et al., “Round Window Gentamicin Absorption: An In Vivo Human Model,” Laryngoscope, Sep. 2002, 112: 1610-1613. [cited by applicant]
Ben-Arie et al., “Math1 is essential for genesis of cerebellar granule neurons.” Nature, 1997, 390: 169-172. [cited by applicant]
Ben-Arie et al., “Functional conservation of atonal and Math1 in the CNS and PNS,” Development, 2000, 127:1039-1048. [cited by applicant]
Bermingham et al., “Math1: An Essential Gene for the Generation of Inner Ear Hair Cells,” Science, 1999, 284: 1837-1841. [cited by applicant]
Bernstein et al., “A bivalent chromatin structure marks key developmental genes in embryonic stem cells,” Cell, Apr. 2006, 125(2):315-326. [cited by applicant]
Bernstein et al., “Methylation ofhistone H3 Lys 4 in coding regions of active genes, ” Proc Natl Acad Sci U S A, Jun. 2002, 99(13):8695-8700. [cited by applicant]
Bertrand et al., “Proneural genes and the specification of neural cell types,” Nature Reviews Neuroscience, 2002, 3:517-530. [cited by applicant]
Beurel et al., “Glycogen synthase kinase-3 (GSIG): Regulation, actions, and diseases,” Pharmacology & Therapeutics, 2015, 148:114-131. [cited by applicant]
Bodson et al., “Hair cell progenitors: identification and regulatory genes,” Acta Otolaryngol, Mar. 2010, 130(3):312-7. [cited by applicant]
Borden et al., “Hyaluronic Acid Hydrogel Sustains the Delivery of Dexamethasone across the Round Window Membrane,” Audiol Neurootol., 2011, 16(1):1-11. [cited by applicant]
Bossuyt et al., “Atonal homolog 1 is a tumor suppressor gene,” PLoS Biology, 2009, 7:e39. [cited by applicant]
Bouchard et al., “Pax2 and homeodomain proteins cooperatively regulate a 435 bp enhancer of the mouse Pax5 gene at the midbrain-hindbrain boundary,” Develop., 127:1017-28 (2000). [cited by applicant]
Bramhall, “Lgr5-Positive Supporting Cells Generate New Hair Cells in the Postnatal Cochlea,” Stem Cell Reports, Mar. 2014, 2:1-12. [cited by applicant]
Breuskin et al., “Strategies to regenerate hair cells: identification of progenitors and critical genes,” Hear Res, 2008, 236(1-2):1-10. [cited by applicant]
Brooker et al., “Notch ligands with contrasting functions: Jaggedl and Deltal in the mouse inner ear,” Development, 2006,133:1277-1286. [cited by applicant]
Brors et al., “EphA4 Provides Repulsive Signals to Developing Cochlear Ganglion Neurites Mediated through Ephrin-B2 and -B3,” J. Comp. Neurol., 462:90-100 (2003). [cited by applicant]
Bryant et al., “Sensory organ development in the inner ear: Molecular and cellular mechanisms,” British Medical Bulletin, 63:39-57 (2002). [cited by applicant]
Burns and Stone, “Development and regeneration of vestibular hair cells in mammals,” Semin Cell Dev Biol, 2017, 65: 96-105. [cited by applicant]
Burns et al, “MYC Gene Delivery to Adult Mouse Utricles Stimulates Proliferation of Postmitotic Supporting Cells In Vitro,” PLOS ONE, Oct. 2012, 7: 248704. [cited by applicant]
Burton et al., “The role of Pax2 in mouse inner ear development,” Dev. Biol., 272:161-175 (2004). [cited by applicant]
CA Office Action in Canadian Appln. No. 2,883,896, dated Jul. 16, 2019, 4 pages. [cited by applicant]
CA Office Action in Canadian Appln. No. 2,883,896, dated Apr. 1, 2021, 4 pages. [cited by applicant]
Cafaro et al., “Atoh1 expression defines activated progenitors and differentiating hair cells during avian hair cell regeneration,” Developmental dynamics, 2007, 236:156-170. [cited by applicant]
Cai et al., “Characterization of the transcriptome of nascent hair cells and identification of direct targets of the Atoh1 transcription factor,” J Neurosci, Apr. 2015, 35(14):5870-5883. [cited by applicant]
Cai et al., “Conditional deletion of Atoh1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti,” The Journal of Neuroscience, 2013, 10110-10122. [cited by applicant]
Caiazzo et al., “Direct generation of functional dopaminergic neurons from mouse and human fibroblasts,” Nature, 476:224-7 (Jul. 2011). [cited by applicant]
Carlisle et al., “Specific expression of Kcna10, Pxn and Odf2 in the organ of Corti,” Gene Expr Patterns, May 2012, 12:172-179. [cited by applicant]
Cau et al., “Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors,” Develop., 124:1611-1621 (1997). [cited by applicant]
Chai et al., “Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea,” PNAS, 2012, 109: 8167-8172. [cited by applicant]
Charron et al., “The Morphogen Sonic Hedgehog is an Axonal Chemoattractant that Collaborates with Netrin-1 in Midline Axon Guidance,” Cell., 113:11-23 (2003). [cited by applicant]
Chen and Segil, “p27 [cited by applicant]
Chen et al., “Histone Demethylase LSD1 Promotes Adipocyte Differentiation through Repressing Wnt Signaling,” Cell Chem Biol, Sep. 2016, 23(10):1228-1240. [cited by applicant]
Chen et al., “ARF-BPI/Mule is a critical mediator of the ARF tumor suppressor,” Cell, 2005. 121: 1071-1083. [cited by applicant]
Chen et al., “The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination,” Develop., 129:2495-2505 (2002). [cited by applicant]
Cheng et al., “Destabilization of Atoh1 by E3 Ubiquitin Ligase Huwel and Casein Kinase Is Essential for Normal Sensory Hair Cell Development,” Journal of Biological Chemistry, Sep. 2016, 291(40):21096-21109. [cited by applicant]
Cheng, “Role Of The Ubiquitin-Proteasome Pathway In The Inner Ear: Identification Of An E3 Ubiquitin Ligase For Atoh1,” Thesis for the Degree of Doctor of Philosophy in Health Sciences and Technology, Harvard-Massachuse… [cited by applicant]
Chim et al., “Deafness associated with the use of Bortezomib in multiple myeloma,” Acta Oncologica, Jan. 2008, 47(2):323-324. [cited by applicant]
Chonko et al., “Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear,” Dev Biol, Sep. 2013, 381(2):401-410. [cited by applicant]
Clevers, “Wnt/beta-catenin signaling in development and disease,” Cell, 2006, 127:469-480. [cited by applicant]
Colter et al., “Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow,” Proc. Natl. Acad. Sci. U.S.A , 97:3213-3218 (2000). [cited by applicant]
Corrales et al., “Engraftment and Differentiation of Embryonic Stem Cell-Derived Neural Progenitor Cells in the Cochlear Nerve Trunk: Growth of Processes into the Organ of Corti,” J. Neurobiol., 66:1489-500 (2006). [cited by applicant]
Corwin et al., “Regeneration of Sensory Hair Cells After Acoustic Trauma,” Science, Jun. 1988, 240:1772-1774. [cited by applicant]
Cosgrove et al., “Integrin alphalbetal and transforming growth factor-beta1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy,” Am. J. Pathol., 157:1649-59 (2000). [cited by applicant]
Cox et al., “Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo,” Development, 2014, 141: 816-829. [cited by applicant]
Crowder and Freeman, “Glycogen Synthase Kinase-3b Activity Is Critical for Neuronal Death Caused by Inhibiting Phosphatidylinositol 3-Kinase or Akt but Not for Death Caused by Nerve Growth Factor Withdrawal,” The Journa… [cited by applicant]
Dabdoub et al., “Abstract # 443: WNt/B-Catenin Signaling in the Developing Mammalian Cochlea,” ARO 31st Annual Midwinter Meeting, Phoenix, Arizona, Feb. 16-21, 2008, 3 pages. [cited by applicant]
Dabdoub et al., “Abstract # 8: Wnt Signaling in the Developing Mammalian Cochlea,” ARO 30th Annual Midwinter Meeting, Denver, Colorado, Feb. 10-15, 2007, 2 pages. [cited by applicant]
D'Arca et al., “Huwe 1 ubiquitin ligase is essential to synchronize neuronal and glial differentiation in the developing cerebellum,” PNAS, 2010, 107:5875-5880. [cited by applicant]
Daudet and Lewis, “Two contrasting roles for Notch activity in chick inner ear development: specification of pro sensory patches and lateral inhibition of hair-cell differentiation,” Development, 132:541-51 (Feb. 2005). [cited by applicant]
Daudet et al., “Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds,” Dev Biol., 326(1):86-100 (Feb. 1, 2009). [cited by applicant]
Davis, “Hearing disorders in the population: first phase findings of the MRC National Study of Hearing,” Hearing Science and Hearing Disorders, 1983, 35-60. [cited by applicant]
De Groot et al., “Huwel-mediated ubiquitylation of dishevelled defines a negative feedback loop in the Wnt signaling pathway,” Science Signaling, Mar. 2014, 7:ra26. [cited by applicant]
Declaration of Non-Establishment of International Search Report for PCT/US2009/065747, mailed Apr. 8, 2010. [cited by applicant]
Deshaies and Joazeiro, “RING domain E3 ubiquitin ligases,” Annual Review of Biochemistry, 2009, 78:399-434. [cited by applicant]
Dezawa et al., “Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation,” J. Clin. Invest., 113:1701-1710 (2004). [cited by applicant]
Dobin et al., “STAR: ultrafast universal RNAseq aligner,” Bioinformatics, Jan. 2013, 29(1):15-21. [cited by applicant]
Doetzlhofer et al., “Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti,” Dev Cell, 16:58-69 (Jan. 2009). [cited by applicant]
Dong et al., “Calpain inhibitor MDL28170 modulates Aβ formation by inhibiting the formation of intermediate Aβ46 and protecting Aβ from degradation,” The FASEB Journal, Dec. 2005, 21 pages. [cited by applicant]
D'Onofrio et al., “Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease,” Expert Opinion on Drug Discovery, Jan. 1, 2012, 7(1):19-37. [cited by applicant]
Doyonnas et al., “Hematopoietic contribution to skeletal muscle regeneration by myelomoncytic precursors,” Proc. Natl. Acad. Sci. U.S.A, 101:13507-13512 (2004). [cited by applicant]
Eatock and Rusch, “Developmental changes in the physiology of hair cells,” Cell & Developmental Biology, 1997, 8:265-275. [cited by applicant]
Edge and Chen, “Hair cell regeneration,” Curr Opin Neurobiol, 2008, 18: 377-382. [cited by applicant]
Edge et al., “Current Applications of Cellular Xenografts,” Trans. Proc., 32:1169-1171 (2000). [cited by applicant]
Eng et al., “An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database,” Journal of the American Society for Mass Spectrometry, 1994, 5:976-989. [cited by applicant]
Escobar-Chávez et al., “Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations,” J Pharm Pharm Sci., 2006, 9(3):339-58. [cited by applicant]
European Search Report in Application No. 13836099, dated Mar. 8, 2016, 9 Pages. [cited by applicant]
Examination Report issued in Australian Patent Application No. 2007334260 on Aug. 23, 2012 (5 pages). [cited by applicant]
Extended European Search Report issued in corresponding European Patent Application No. 07871464.9, mailed Nov. 17, 2010. [cited by applicant]
Extended European Search Report issued in EP 0982830, mailed Dec. 7, 2012. [cited by applicant]
Feng et al., “Blocking caspase-3-dependent pathway preserves hair cells from salicylate-induced apoptosis in the guinea pig cochlea,” Mol Cell Biochem., 2011, 353:291-303. [cited by applicant]
Ferrer-Vaquer et al., “A sensitive and bright single-cell resolution live imaging reporter of Wnt/ss-catenin signaling in the mouse,” BMC Dev Biol, Dec. 2010, 10:121, 18 pages. [cited by applicant]
Final Office Action issued in U.S. Appl. No. 13/130,607 on Oct. 21, 2013, 11 pages. [cited by applicant]
Flora et al., “Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma,” Science, 2009, 326:1424-1427. [cited by applicant]
Flora et al., “The E-protein Tcf4 interacts with Math 1 to regulate differentiation of a specific subset of neuronal progenitors,” PNAS, 2007, 104: 15382-15387. [cited by applicant]
Forge et al., “Hair Cell Recovery in the Vestibular Sensory Epithelia of Mature Guinea Pigs,” The Journal of Comparative Neurology, 1998, 397: 69-88. [cited by applicant]
Forge et al., “Ultrastructural evidence for hair cell regeneration in the mammalian inner ear,” Science, 1993, 259: 1616-1619. [cited by applicant]
Forget et al., “Shh Signaling Protects Atoh1 from Degradation Mediated By The E3 Ubiquitin Ligase Huwel In Neural Precursors,” Developmental Cell, Jun. 2014, 29: 649-661. [cited by applicant]
Forneris et al., “Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process,” FEBS Lett, Apr. 2005, 579(10):2203-2207. [cited by applicant]
Frisina, “Age-related hearing loss: ear and brain mechanisms,” Annals of the New York Academy of Sciences, 2009, 1170: 708-717. [cited by applicant]
Fritzsch et al., “Atoh1 Null Mice Show Directed Afferent Fiber Growth to Undifferentiated Ear Sensory Epithelia Followed by Incomplete Fiber Retention,” Dev. Dyn., 233:570-583 (2005). [cited by applicant]
Fritzsch et al., “Lack of Neurotrophin 3 Causes Losses of Both Classes of Spiral Ganglion Neurons in the Cochlea in a Region-Specific Fashion,” J. Neurosci., 17:6213-6225 (1997). [cited by applicant]
Fritzsch, “Development of inner ear afferent connections: forming primaly neurons and connecting them to the developing sensory epithelia,” Brain Research Bulletin, 2003, 60:423-433. [cited by applicant]
Fuerer and Nusse, “Lentiviral vectors to probe and manipulate the Wnt signaling pathway,” PLoS One, 2010, 5(2):e9370, 7 pages. [cited by applicant]
Fujioka et al., “SY3A-H5 A novel y-secretase inhibitor, LY411575, replaced auditory hair cells and recovered hearing loss after severe acoustic trauma in mice,” Neurosci Res., 2008, 61(Suppl):S25. [cited by applicant]
Fujioka et al., “In vivo differentiation toward hair cell: A novel gamma-secretase inhibitor, LY411575, replaced auditory hair cells and ameliorated hearing impairment after severe acoustic trauma in mice,” Presented at… [cited by applicant]
Fujioka et al., “Manipulating cell fate in the cochlea: a feasible therapy for hearing loss,” Trends Neurosci, 2015, 38: 139-144. [cited by applicant]
Gage, “Cell therapy,” Nature, 392(6679 Suppl):18-24 (1998). [cited by applicant]
Gao et al., “mTOR drives its own activation via SCF(˜TrCP)dependent degradation of the mTOR inhibitor DEPTOR,” Molecular Cell, 2011, 44:290-303. [cited by applicant]
Gao et al., “Quantitative imaging of cochlear soft tissues in wild-type and hearingimpaired transgenic mice by spectral domain optical coherence tomography,” Optics Express, 2011, 19:15415-15428. [cited by applicant]
Garapaty-Rao et al., “Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth,” Chem. Biol, 2013, 20(11):1329-1339. [cited by applicant]
Ge et al., “Distribution of PLGA nanoparticles in chinchilla cochleae,” Otolaryngol Head Neck Surg., Oct. 2007, 137(4):619-23. [cited by applicant]
Geling et al., “A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish,” EMBO report, 2002, 688-694. [cited by applicant]
Geng et al., “Comprehensive Expression of Wnt Signaling Pathway Genes during Development and Maturation of the Mouse Cochlea,” PLoS One, Feb. 2016, 11(2):e0148339, 18 pages. [cited by applicant]
Gillespie et al., “LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro,” Neuro. Rep., 12:275-279 (2001). [cited by applicant]
Golub et al., “Hair Cell Replacement in Adult Mouse Utricles after Targeted Ablation of Hair Cells with Diphtheria Toxin,” The Journal of Neuroscience, Oct. 2012, 32: 15093-15105. [cited by applicant]
Gowan et al., “Crossinhibitory Activities of Ngn1 and Math1 Allow Specification of Distinct Dorsal Interneurons,” Neuron., 31:219-232 (2001). [cited by applicant]
Goycoolea and Lundman, “Round window membrane. Structure function and permeability: a review,” Microsc Res Tech., 36:201-11 (Feb. 1, 1997). [cited by applicant]
Gregorieff and Clevers, “Wnt signaling in the intestinal epithelium: from endoderm to cancer,” Genes & Development, 2005, 19:877-890. [cited by applicant]
Groves, “The challenge of hair cell regeneration,” Exp Biol Med (Maywood), Apr. 2010, 235(4):434-446. [cited by applicant]
Gubbels et al., “Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer,” Nature, 2008, 455:537-541. [cited by applicant]
Guo et al., “Targeting the Notch signaling pathway in cancer therapeutics,” Thoracic Cancer, 2014, 5: 473-486. [cited by applicant]
Haapasalo and Kovacs; “The Many Substrates of Presenilin/γ-Secretase” Journal Alzheimers Disease. 2011: 25(1): 3-28. [cited by applicant]
Hadland et al., “γ-secretase inhibitors repress thymocyte development,” Proc Natl. Acad Sci USA, 98:7487-91 (Jun. 19, 2001). [cited by applicant]
Han and Shen, “Targeting γ-secretase in breast cancer,” Breast Cancer: Targets and Therapy, 2012, 2012: 83-90. [cited by applicant]
Hanna et al., “Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues,” Cell, Nov. 2010, 143(4):508-525. [cited by applicant]
Hartman et al., “Hes5 expression in the postnatal and adult mouse inner ear and the drug-damaged cochlea,” J Assoc Res Otolaryngol., 10:321-40 (Sep. 2009). [cited by applicant]
Havenith et al., “Spiral ganglion cell survival after round window membrane application of brain-derived neurotrophic factor using gelfoam as carrier,” Hearing Research, Feb. 2011, 272(1-2):168-177. [cited by applicant]
Hawkins et al., “The developmental genetics of auditory hair cells,” Hum. Mol. Genet., 13:R289-296 (2004). [cited by applicant]
Heintzman et al., “Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome,” Nat Genet, Mar. 2007, 39(3):311-318. [cited by applicant]
Heller et al., “Parvalbumin 3 is an Abundant Ca2+ Buffer in Hair Cells,” J. Assoc. Res. Otolaryngol., 3:488-498 (2002). [cited by applicant]
Helms et al., “Autoregulation and multiple enhancers control Math1 expression in the developing nervous system,” Develop., 127:1185-1196 (2000). [cited by applicant]
Helms et al., “Overexpression of MATH1 Disrupts the Coordination of Neural Differentiation in Cerebellum Development,” Mol. Cell. Neurosci., 17:671-682 (2001). [cited by applicant]
Hendrickx & Leyns, “Non-conventional Frizzled ligands and Wnt receptors,” Develop Growth Differ., 2008, 50:229-243. [cited by applicant]
Hermann et al., “Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells,” J. Cell. Sci., 117:4411-4422 (2004). [cited by applicant]
Herold et al., “Miz1 and HectH9 regulate the stability of the checkpoint protein, TopBP1,” The EMBO Journal, 2008, 27:2851-2861. [cited by applicant]
Herzog et al., “Plasticity of marrow-derived stem cells,” Blood, 102:3483-3493 (2003). [cited by applicant]
Hess et al., “Bone marrow-derived stem cells initiate pancreatic regeneration,” Nat. Biotechnol., 21:763-770 (2003). [cited by applicant]
Hildebrand et al, “Advances in Molecular and Cellular Therapies for Hearing Loss,” Molecular Therapy, 2008, 16(2):224-236. [cited by applicant]
Hirabayashi et al., “The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells,” Development, 2004, 131: 2791-2801. [cited by applicant]
Hödar et al., “Genome-wide identification of new Wnt/beta-catenin target genes in the human genome using CART method,” BMC Genomics, 2010, 11:348, 15 pages. [cited by applicant]
Horie et al., “Sustained delivery of lidocaine into the cochlea using poly lactic/glycolic acid microparticles,” Laryngoscope, 2010, 120(2):377-83. [cited by applicant]
Hosoya et al., “Method for efficient screening of substances inducing differentiation into inner ear hair cells with the use of spheres derived from inner ear cells,” Otol Jpn, 2008, 18(4): 275 (with English translation… [cited by applicant]
Hosoya et al., “An efficient screening method using inner-ear derived spheres for selection of compounds that induce hair cell differentiation,” Neurosci. Res., 2008, 61S:S57 Abstract, 2 pages. [cited by applicant]
Hu and Ulfendahl, “Cell replacement therapy in the inner ear,” Stem Cell and Development, 15:449-459 (2006). [cited by applicant]
Hu et al., “Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice,” J Neurosci, 2016, 36:9479-9489. [cited by applicant]
Hu et al., “Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells,” Gastroenterology, Nov. 2007, 133(5):1579-1591. [cited by applicant]
Hu et al., “Neural cograft stimulates the survival and differentiation of embryonic stem cells in the adult mammalian auditory System,” Brain Research, 2005, 1051:137-144. [cited by applicant]
Hu et al., “Survival and neural differentiation of adult neural stem cells transplanted into the mature inner ear,” Exper. Cell. Res., 302:40-47 (2005). [cited by applicant]
Huang et al., “Lysine 63-linked polyubiquitination is required for EGF receptor degradation,” PNAS, Sep. 2013, 110(39):15722-15727. [cited by applicant]
Huang, “Age-related hearing loss,” Minn Med, 2007, 90(10):48-50. [cited by applicant]
Huibregtse et al., A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase, PNAS, 1995, 92:5249. [cited by applicant]
Hume et al., “Expression of LHX3 and SOX2 during mouse inner ear development,” Gene Expression Patterns, 2007, 7:798-807. [cited by applicant]
Husseman and Raphael, Gene therapy in the inner ear using adenovirus vectors. Advances in Oto-Rhino-Laryngology, 2009, 66:37-51. [cited by applicant]
Huynh et al., “The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma,” PLoS One, 6(9):e25264, (2011) 10 pages. [cited by applicant]
Hyde et al., “Studies to investigate the in vivo therapeutic window of the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alani… [cited by applicant]
Hyun et al., “In Vitro and in Vivo Release of Albumin Using a Biodegradable MPEG-PCL Diblock Copolymer as an in Situ Gel-Forming Carrier,” Biomacromolecules, Apr. 2007, 8(4):1093-100. [cited by applicant]
Ikeda and Dikic, “Atypical ubiquitin chains: new molecular signals. “Protein Modifications: Beyond the Usual Suspects” review series,” EMBO Reports, 2008, 9:536-542. [cited by applicant]
Inaoka et al., “Local application of hepatocyte growth factor using gelatin hydrogels attenuates noise-induced hearing loss in guinea pigs,” Acta Otolaryngol., Apr. 2009, 129(4):453-7. [cited by applicant]
Incesulu and Nadal, “Correlation of acoustic threshold measures and spiral ganglion cell survival in severe to profound sensorineural hearing loss: implications for cochlear implantation,” The Annals of Otology, Rhinolo… [cited by applicant]
Inoue et al., “Mule/Huwel/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation ofp21 and p15,” Genes & Development, 2013, 27: 1101-1114. [cited by applicant]
International Preliminary Report on Patentability for PCT/US2009/065747, issued May 24, 2011. [cited by applicant]
International Preliminary Report on Patentability in International Application No. PCT/US2013/058446, issued Mar. 10, 2015, 11 pages. [cited by applicant]
International Preliminary Report on Patentability in International Application No. PCT/US2016/064727, mailed on Jun. 14, 2018, 9 pages. [cited by applicant]
International Preliminary Report on Patentability in International Application No. PCT/US2017/015379, mailed on Aug. 9, 2018, 11 pages. [cited by applicant]
International Preliminary Report on Patentability in International Appln. No. PCT/US2019/063418, mailed on Jun. 10, 2021, 9 pages. [cited by applicant]
International Preliminary Report on Patentability issued in corresponding International Application No. PCT/US2007/084654, mailed May 28, 2009. [cited by applicant]
International Search Report and Written Opinion in International Application No. PCT/US15/43976, mailed on Jan. 20, 2016, 16 pages. [cited by applicant]
International Search Report and Written Opinion in International Application No. PCT/US2013/058446, mailed Dec. 26, 2013, 8 pages. [cited by applicant]
International Search Report and Written Opinion in International Application No. PCT/US2016/064727, mailed on May 1, 2017, 18 pages. [cited by applicant]
International Search Report and Written Opinion in International application No. PCT/US2017/015379, mailed on May 31, 2017, 18 pages. [cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/US2019/063418, mailed on Apr. 23, 2020, 12 pages. [cited by applicant]
International Search Report issued in corresponding International Application No. PCT/US2007/84654, mailed Oct. 3, 2008. [cited by applicant]
Inuzuka et al., “SCFFBW7 regulates cellular apoptosis by targeting MCLI for ubiquitylation and destruction,” Nature, 2012, 470:104-109. [cited by applicant]
Invitation to Pay Additional Fees And, Where Applicable, Protest Fee in International Appln. No. PCT/US2019/063418, mailed on Feb. 24, 2020, 2 pages. [cited by applicant]
Ito et al., “Neurotrophins Facilitate Neuronal Differentiation of Cultured Neural Stem Cells Via Induction of mRNA Expression of Basic Helix-Loop-Helix Transcription Factors Mash1 and Math1,” J. Neurosci. Res., 71:648-6… [cited by applicant]
Ivan et al., “HIFalpha targeted for VHL-mediated destruction by praline hydroxylation: implications for 02 sensing,” Science, 2001,292:464-468. [cited by applicant]
Ivanov et al., “Genes required for [cited by applicant]
Izumikawa et al., “Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals,” Nat Med., 11(3)271-6 (Mar. 2005). [cited by applicant]
Jaakkola et al., “Targeting ofHIF-alpha to the von Hippel-Lindau ubiquitylation complex by 02-regulated prolyl hydroxylation,” Science, 2001, 292:468-472. [cited by applicant]
Jacques et al., “A dual function for canonical Wnt/beta-catenin signaling in the developing mammalian cochlea,” Development, Dec. 2012, 139(23):4395-4404, 18 pages. [cited by applicant]
Jaenisch and Bird, “Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals,” Nat Genet, Mar. 2003, 33 Suppl:245-254. [cited by applicant]
Jahan et al., “Beyond generalized hair cells: molecular cues for hair cell types,” Hear Res, Mar. 2013, 297:30-41. [cited by applicant]
Jarriault et al., “Delta-1 Activation of Notch-1 Signaling Results in HES-1 Transactivation,” Mol. Cell. Biol, 1998, 18:7423-7431. [cited by applicant]
Jarriault et al., “Signalling downstream of activated mammalian Notch,” Nature, 1995, 377:355-358. [cited by applicant]
Jeon et al., “Notch Signaling Alters Sensory or Neuronal Cell Fate Specification of Inner Ear Stem Cells,” J. Neurosci, 2011, 31: 8351-8358. [cited by applicant]
Jeon et al., “Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells,” Molecular and Cellular Neurosciences, 34:59-68 (2007). [cited by applicant]
Jiang et al., “Neuroectodermal differentiation from mouse multipotent adult progenitor cells,” Proc. Natl. Acad. Sci .U.S.A, 100:11854-11860 (2003). [cited by applicant]
Jiang et al., “Pluripotency of mesenchymal stem cells derived from adult marrow,” Nature, 418:41-49 (2002). [cited by applicant]
Jin et al., “Systematic analysis and nomenclature of mammalian F-box proteins,” Genes Dev, 2004, 18(21):2573-2580. [cited by applicant]
Jorstad et al., “Stimulation of functional neuronal regeneration from Müller glia in adult mice,” Nature, Aug. 2017, 548(7665):103-107. [cited by applicant]
Kaneko et al., “Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells,” Dev Neurosci., 22:139-53 (2000). [cited by applicant]
Kawamoto et al., “Spontaneous hair cell regeneration in the mouse utricle following gentamicin ototoxicity,” Hearing Research, 2009, 247: 17-26. [cited by applicant]
Kearns et al., “Functional annotation of native enhancers with a Cas9-histone demethylase fusion,” Nat Methods, 2015, 12:401-403, 6 pages. [cited by applicant]
Kehrle et al., “Comparison of Auditory Brainstem Response Results in Normal-Hearing Patients With and Without Tinnitus,” Arch Otolaryngol Head Neck Surg., 2008, 134(6):647-651. [cited by applicant]
Kelley et al., “Regulation of cell fate in the sensory epithelia of the inner ear,” Nat Rev Neurosci, 2006, 7: 837-849. [cited by applicant]
Kerenyi et al., “Histone demethylase LSD1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation,” eLife, 2013, 2:e00633, 23 pages. [cited by applicant]
Kicic et al., “Differentiation of Marrow Stromal Cells into Photoreceptors in the Rat Eye,” J. Neurosci., 23:7742-7749 (2003). [cited by applicant]
Kiernan et al., “Sox2 is required for sensory organ development in the mammalian inner ear,” Nature, 434:1031-1035 (2005). [cited by applicant]
Kim et al., “Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease,” Nature, 418:50-6 (2002). [cited by applicant]
Kim et al., “NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development,” Develop., 128:417-426 (2001). [cited by applicant]
Klisch et al., “In vivo Atoh1 targetome reveals how a proneural transcription factor regulates cerebellar development,” PNAS, 2011, 108(8):3288-3293. [cited by applicant]
Knippschild et al., “Metaanalysis to Estimate the Expected Drop Out-Rates Reported in Clinical Trials on Cataract Surgery,” 2014, 231: 151-157 (with English abstract). [cited by applicant]
Knippschild et al., “The CK1 family: contribution to cellular stress response and its role in carcinogenesis,” Frontiers in Oncology, May 2014, 4: 32 pages. [cited by applicant]
Koch et al., “The landscape of histone modifications across 1% of the human genome in five human cell lines,” Genome Res, 2007, 17(6):691-707. [cited by applicant]
Kondo et al., “Sonic Hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells,” Proc. Natl. Acad. Sci. U.S.A., 102(13):4789-4794 (Mar. 2005). [cited by applicant]
Kondo et al., “Wnt Signaling Promotes Neuronal Differentiation From Mesenchymal Stem Cells Through Activation ofTlx3,” Stem Cells, 2011, 29(5):836-46. [cited by applicant]
Kopan et al., “The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism,” Cell, 2009, 137:216-233. [cited by applicant]
Kurokawa et al., “A network of substrates of the E3 ubiquitin ligases MDM2 and HUWEI control apoptosis independently ofp53,” Science Signaling, 2013, 6:ra32. [cited by applicant]
Lanford et al., “Notch signalling pathway mediates hair cell development in mammalian cochlea,” Nature Genetics, 21:289-292 (1999). [cited by applicant]
Lang et al., “Contribution of Bone Marrow Hematopoietic Stem Cells to Adult Mouse Inner Ear: Mesenchymal Cells and Fibrocytes,” J .Comp. Neurol., 496:187-201 (2006). [cited by applicant]
Lanzoni et al., “MDL 28170 Attenuates Gentamicin Ototoxicity,” Audiological Medicine, 2005, 3:82-89. [cited by applicant]
Latres et al., “The human F box protein beta-Trcp associates with the Cull/Skp1 complex and regulates the stability of beta-catenin,” Oncogene, Jan. 1999, 18:849-854. [cited by applicant]
Laurent et al., “A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation,” Mol Cell, Mar. 2015, 57(6):957-970. [cited by applicant]
Ledent et al., “Phylogenetic analysis of the human basic helix-loop-helix proteins,” Genome Biology, 2002 3:research0030.1. [cited by applicant]
Lee et al., “Proteasome inhibitors induce auditory hair cell death through peroxisome dysfunction,” Biochem. Biophys. Res. Comm., Jan. 2015, 456(1):269-274. [cited by applicant]
Lee et al., “Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells,” Nat. Biotech., 18:675-9, (2000). [cited by applicant]
Lee et al., “EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex,” Molecular Cell, 2012, 48:572-586. [cited by applicant]
Lei et al., “Lysine-specific demethylase 1 promotes the sternness and chemoresistance of Lgr5(+) liver cancer initiating cells by suppressing negative regulators of beta-catenin signaling,” Oncogene, Jun. 2015, 34(24):3… [cited by applicant]
Leon et al., “Insulin-Like Growth Factor-I Regulates Cell Proliferation in the Developing Inner Ear, Activating Glycosyl-Phosphatidylinositol Hydrolysis and Fos Expression,” Endocrinol., 136:3494-3503 (1995). [cited by applicant]
Li et al., “Round Window Membrane Delivery of L-Methionine Provides Protection from Cisplatin Ototoxicity Without Compromising Chemotherapeutic Efficacy,” Neuro Toxicology, 2001, 22:163-176. [cited by applicant]
Li et al., “Correlation of Pax-2 Expression with Cell Proliferation in the Developing Chicken Inner Ear,” J. Neurobiol., 60:61-70 (2004). [cited by applicant]
Li et al., “Generation of hair cells by stepwise differentiation of embryonic stem cells,” Proc. Natl. Acad. Sci. U.S.A. Nov. 2003, 100(23):13495-13500. [cited by applicant]
Li et al., “Pluripotent stem cells from the adult mouse inner ear,” Nat. Med., 9:1293-1299 (2003). [cited by applicant]
Li et al., “Specification of motoneurons from human embryonic stem cells,” Nat. Biotechnol., 23:215-21 (2005). [cited by applicant]
Li et al., “Stem cells as therapy for hearing loss,” Trends Mol. Med., 10:309-315 (2004). [cited by applicant]
Lin et al., “Hair cell damage recruited Lgr5-expressing cells are hair cell progenitors in neonatal mouse utricle,” Front Cell Neurosci, Apr. 2015, 9: 1-11. [cited by applicant]
Lin et al., “Inhibition of notch activity promotes non-mitotic regeneration of hair cells in the adult mouse utricles,” J Neurosci., 31(43):15329-15339 (Oct. 26, 2011). [cited by applicant]
Lo et al., “Mammalian achaete-scute homolog 1 is transiently expressed by spatially restricted subsets of early neuroepithelial and neural crest cells,” Genes & Development, 1991, 5: 1524-1537. [cited by applicant]
Loo et al., “From short peptides to nanofibers to macromolecular assemblies in biomedicine,” Biotechnol Adv., 2012, 30(3):593-603. [cited by applicant]
Loseva et al, “Comparison of reactive processes in the rat brain elicited by xenotransplantation of nervous tissues of chicken or pulmonate snail,” Brain Research, 2001, 915:125-132. [cited by applicant]
Love et al., “Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2,” Genome Biol, 2014, 15(12):550, 21 pages. [cited by applicant]
Lu et al., “Abstract #: 774: The Influence of Glycogen Synthase Kinase 3 On Cell Proliferation in the Murine Vestibular Sensory Epithelium,” ARO 31st Annual Midwinter Meeting, Phoenix, Arizona, Feb. 16-21, 2008, 3 pages. [cited by applicant]
Lu et al., “The Influence of Glycogen Synthase Kinase 3 in Limiting Cell Addition in the Mammalian Ear,” Develop. Neurobiol., 68:1059-1075 (2008). [cited by applicant]
Luistro et al., “Preclinical Profile of a Potent γ-Secretase Inhibitor Targeting Notch Signaling with In vivo Efficacy and Pharmacodynamic Properties,” Cancer Res, Oct. 2009, 69(19):7672-7690. [cited by applicant]
Lumpkin et al., “Math1-driven GFP expression in the developing nervous system of transgenic mice,” Gene Expr Patterns, 3:389-95 (Aug. 2003). [cited by applicant]
Ma and Raible, “Signaling pathways regulating zebrafish lateral line development,” Current Biology, 2009, 19:R381-386. [cited by applicant]
Ma et al., “Neurogenin 1 Null Mutant Ears Develop Fewer, Morphologically Normal Hair Cells in Smaller Sensory Epithelia Devoid of Innervation,” Assoc. Res. Otolaryngol., 1:129-143 (2000). [cited by applicant]
Madisen et al., “A robust and high-throughput Cre reporting and characterization system for the whole mouse brain,” Nat Neurosci, 2010, 13: 133-140. [cited by applicant]
Maiques-Diaz et al., “Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia,” Cell Rep, Mar. 2018, 22:3641-3659, 40 pages. [cited by applicant]
Maksimovic et al., “Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors,” Nature, 2014, 509:617-621. [cited by applicant]
Mangi et al., “Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts,” Nat. Med., 9:1195-201 (2003). [cited by applicant]
Markkanen et al., “Regulation of oxidative DNA damage repair by DNA polymerase A and MutYH by cross-talk of phosphorylation and ubiquitination,” PNAS, 2012, 109:437-442. [cited by applicant]
Maru et al., “Lentivirus-Based Stable Gene Delivery into Intestinal Organoids,” Methods Mol Biol, 2016, 1422:13-21. [cited by applicant]
Masuda et al., “Dual antitumor mechanisms of notch signaling inhibitor in a T-cell acute lymphoblastic leukemia xenograft model,” Cancer Sci., 100(12):2444-2450 (Dec. 2009). [cited by applicant]
Matei et al., “Smaller Inner Ear Sensory Epithelia in Neurog1 Null Mice Are Related to Earlier Hair Cell Cycle Exit,” Dev. Dyn., 234:633-50 (2005). [cited by applicant]
Matsui et al., “Regeneration and replacement in the vertebrate inner ear,” Drug Discov. Today, 10:1307-12 (2005). [cited by applicant]
Matsuoka et al., In Vivo and In Vitro Characterization of Bone Marrow-Derived Stem Cells in the Cochlea, Laryngoscope, Aug. 2006, 116:1363-1367. [cited by applicant]
McLean et al., “Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells,” Cell Reports, Feb. 2017, 18(8):1917-1929. [cited by applicant]
Meierhofer et al., “Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry,” Journal of Proteome Research, 2008, 7:4566-4576. [cited by applicant]
Metzger et al., “LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription,” Nature, Sep. 2005, 437(7057):436-439, 5 pages. [cited by applicant]
Mezey et al., “Transplanted bone marrow generates new neurons in human brains,” Proc. Natl. Acad. Sci. U.S.A., 100:1364-1369 (2003). [cited by applicant]
Miesegaes et al., “Identification and subclassification of new Atohl derived cell populations during mouse spinal cord development,” Developmental Biology, Mar. 2009, 327:339-351. [cited by applicant]
Mikulec et al., “Permeability of the round window membrane is influenced by the composition of applied drug solutions and by common surgical procedures,” Otol Neurotol., 29:1020-6 (Oct. 2008). [cited by applicant]
Mitani et al., “Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice,” J. Neuroscience, Feb. 2012. [cited by applicant]
Mizutari et al., “Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma,” Neuron, 2013, 77: 58-69. [cited by applicant]
Moon et al., “WNT and B-catenin signalling: diseases and therapies,” Nature Reviews, Sep. 2004, 5: 689-699. [cited by applicant]
Moore et al., “Modulation of Wnt Signaling Through Inhibition of Secreted Frizzled-Related Protein I (sFRP-1) with N-Substituted Piperidinyl Diphenylsulfonyl Sulfonamides,” J Med.Chem., 2009, 52(1):105-116. [cited by applicant]
Morrison et al., “Mammalian Merkel cells are descended from the epidermal lineage,” Developmental Biology, 2009, 336:76-83. [cited by applicant]
Murre et al., “Interactions between heterologous helixloop-helix proteins generate complexes that bind specifically to a common DNA sequence.,” Cell, 1989, 58:537-544. [cited by applicant]
Murry et al., “Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts,” Nature., 428:664-668 (2004). [cited by applicant]
Nadol, Jr. et al., “Degenerative Changes in the Organ of Corti and Lateral Cochlear Wall in Experimental Endolymphatic Hydrops and Human Meniere's Disease,” Acta Otolaryngol, 1995, Suppl 519: 47-59. [cited by applicant]
Naito Yasushi et al., “Transplantation of bone marrow stromal cells into the cochlea of chinchillas,” NeuroReport, Lippincott Williams & Wilkins, 15:1-4 (2004). [cited by applicant]
Nakagawa, “Aiming for the treatment of inner ear diseases—the forefront of basic research,” Bulletin of the Japan Otolaryngology Society, 2008, 11(10):655-663 (with machine abstract). [cited by applicant]
Naujokat and Saric, “Concise review: role and function of the ubiquitinproteasome system in mammalian stem and progenitor cells,” Stem Cells, 2007, 25 :2408-2418. [cited by applicant]
Non-Final Office Action issued in U.S. Appl. No. 13/130,607 on Apr. 19, 2013, 11 pages. [cited by applicant]
Non-Final Office Action issued in U.S. Appl. No. 13/130,607 on Oct. 23, 2014, 12 pages. [cited by applicant]
Notice of Opposition to European Patent in European Application No. 09828380.7, dated Jan. 11, 2018, 39 pages. [cited by applicant]
Noy et al., “HUWE1 ubiquitinates MyoD and targets it for proteasomal degradation,” Biochemical and Biophysical Research Communications, 2012, 418:408-413. [cited by applicant]
Ocampo et al., “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming,” Cell, Dec. 2016, 167(7):1719-1733.e12, 28 pages. [cited by applicant]
Oesterle et al., “Sox2 and JAGGED1 expression in normal and drug-damaged adult mouse inner ear,” J Assoc Res Otolaryngol., 9:65-89 (Mar. 2008). [cited by applicant]
Office Action in European Application No. 13836099.5, dated Jul. 25, 2018, 5 pages. [cited by applicant]
Office Action in Japanese Application No. 2015-178811, dated Jun. 5, 2018, 12 pages (with English translation). [cited by applicant]
Office Action in Japanese Application No. 2015-178811, dated Oct. 17, 2017, 6 pages (with English translation). [cited by applicant]
Office Action in Japanese Application No. 2015-531223, dated Jan. 15, 2019, 6 pages (with English translation). [cited by applicant]
Office Action in Japanese Application No. 2015-531223, dated Jul. 11, 2017, 8 pages (with English translation). [cited by applicant]
Office Action in Japanese Application No. 2015-531223, dated Jun. 19, 2018, 7 pages (with English translation). [cited by applicant]
Office Action issued in AU2009316264 on Jan. 16, 2015 (5 pages). [cited by applicant]
Office Action issued in CA2,669,693 on Apr. 4, 2014 (4 pages). [cited by applicant]
Office Action issued in EP07871464.9 on May 6, 2014 (5 pages). [cited by applicant]
Office Action issued in European Application No. 09828380.7 on Mar. 26, 2014 (6 pages). [cited by applicant]
Office Action issued in Japanese Application No. 2011-537715 issued on Feb. 4, 2014 (translation) 4 pages. [cited by applicant]
Office Action issued in JP2009-537328 on Feb. 12, 2013 (7 pages). [cited by applicant]
Office Action issued in JP2011-537715 on Jan. 20, 2015 with English translation (7 pages). [cited by applicant]
Office Action issued in JP2015-178811 on Mar. 7, 2017 with English translation (5 pages). [cited by applicant]
Ohyama et al., “Wnt signals mediate a fate decision between otic placode and epidermis,” Development, 2006, 133:865-875. [cited by applicant]
Okubo and Hogan, “Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm,” Journal of Biology, 2004, 3: 11. [cited by applicant]
Orford et al., “Differential H3K4 methylation identifies developmentally poised hematopoietic genes,” Dev Cell, May 2008, 14(5):798-809. [cited by applicant]
Oshima et al., “Differential distribution of stem cells in the auditory and vestibular organs of the inner ear,” J Assoc Res Otolaryngol., 8:18-31 (Mar. 2007). [cited by applicant]
Oshima et al., “Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells,” Cell, 2010, 141(4): 704-716. [cited by applicant]
Pagani et al., “Autologous Skeletal Myoblasts Transplanted to Ischemia-Damaged Myocardium in Humans,” J. Am. Coll. Cardiol., 41:879-888 (2003). [cited by applicant]
Pan et al., “Understanding the evolution and development of neurosensory transcription factors of the ear to enhance therapeutic translation,” Cell Tissue Res, Jun. 2012, 349:415-432. [cited by applicant]
Pan et al., “A novel Atoh1 “self-terminating” mouse model reveals the necessity of proper Atoh1 level and duration for hair cell differentiation and viability,” PloS One, 2012, 7:e30358. [cited by applicant]
Pandya et al., “A structural element within the HUWE1 HECT domain modulates self-ubiquitination and substrate ubiquitination activities,” The Journal of Biological Chemistry, 2010, 285:5664-5673. [cited by applicant]
Park et al., “H3K27 Demethylase JMJD3 Employs the NF-kappaB and BMP Signaling Pathways to Modulate the Tumor Microenvironment and Promote Melanoma Progression and Metastasis,” Cancer Res, Jan. 2016, 76(1):161-170. [cited by applicant]
Parker et al., “An independent construct for conditional expression of atonal homolog-1,” Human Gene Therapy Methods, 2014, 25:1-13. [cited by applicant]
Parker et al., “Primary culture and plasmid electroporation of the murine organ of Corti,” Journal of Visualized Experiments, 2010. [cited by applicant]