Granted Patent
B2
US 12,239,651 · App. 18/609,604 · Granted Mar 4, 2025
Treatment of hearing loss
Assignee:
Massachusetts Eye and Ear Infirmary
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Abstract
Compositions for regeneration of inner cells and for treating hearing loss comprise at least one modulator of mechanistic target of rapamycin (mTOR) sufficient to induce reprogramming proliferation and regeneration of inner ear cells. The composition include, in some instances, an effective amount of one or more phosphatase and tensin homolog (PTEN) inhibitors, MYC/NOTCH modulators, Atonal Homolog 1 (Atoh1) modulators or combinations thereof.
Claims (11)
1. A method of regenerating inner ear cells in mature mammalian cochlea in a subject in need thereof, comprising contacting the cochlea with an effective amount of at least one activator of mechanistic target of rapamycin (mTOR) and at least one activator of NOTCH sufficient to induce reprogramming proliferation and regeneration of inner ear cells; thereby regenerating the inner ear cells in mature mammalian cochlea,
wherein the mTOR activator comprises mhy 1485, 3-benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2 (3H)-one (3BDO), salidroside, or polynucleotides encoding mTOR, and
wherein the NOTCH activator comprises NOTCH protein, NOTCH peptides, NOTCH intracellular domain (NICD) peptides, or polynucleotides encoding NOTCH protein, NOTCH peptides, or NICD peptides.
2. The method of claim 1 , wherein inner ear cells comprise: inner ear cells comprise: stria vascularis, hair cells, supporting cells or ganglion neurons.
3. The method of claim 1 , further comprising administering one or more phosphatase and tensin homolog (PTEN) inhibitors, and/or Atonal Homolog 1 (Atoh1) activators, wherein the Atoh1 activators comprise β-catenin or Atoh1 polynucleotides.
4. The method of claim 3 , wherein one or more PTEN inhibitors comprise: bpV(phen), bpV(pic), VO-OHpic, SF1670, antibodies, antibody fragments, antisense oligonucleotides, or siRNAs.
5. A composition comprising an effective amount of least one activator of mechanistic target of rapamycin (mTOR) and at least one activator of NOTCH,
wherein the mTOR activator comprises mhy 1485, 3-benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2 (3H)-one (3BDO), salidroside, or polynucleotides encoding mTOR, and
wherein the NOTCH activator comprises NOTCH protein, NOTCH peptides, NOTCH intracellular domain (NICD) peptides, or polynucleotides encoding NOTCH protein, NOTCH peptides, or NICD peptides.
6. The composition of claim 5 , further comprising an effective amount of one or more phosphatase and tensin homolog (PTEN) inhibitors, and/or Atonal Homolog 1 (Atoh1) activators, wherein the Atoh1 activators comprise β-catenin or Atoh1 polynucleotides.
7. The composition of claim 6 , wherein one or more PTEN inhibitors comprise: bpV(phen), bpV(pic), VO-OHpic, SF1670, antibodies, antibody fragments, antisense oligonucleotides, or siRNAs.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 16, 2024
From: CHEN, ZHENG-YI; LI, WENYAN; QUAN, YI-ZHOU
To: MASSACHUSETTS EYE AND EAR INFIRMARY
Reel/Frame 067429/0606 →
Continuity (4)
Continuation
16964882
Provisional Application
62622598
· Jan 26, 2018
References Cited (143)
US 6417185B1
· Goff et al.
· 2002
[cited by applicant]
US 6489344B1
· Nuss et al.
· 2002
[cited by applicant]
US 6541466B2
· Wu et al.
· 2003
[cited by applicant]
US 6608063B2
· Nuss et al.
· 2003
[cited by applicant]
US 7206639B2
· Jacobsen et al.
· 2007
[cited by applicant]
US 7300951B2
· Kreft et al.
· 2007
[cited by applicant]
US 7468365B2
· Audia et al.
· 2008
[cited by applicant]
US 7544511B2
· Yang et al.
· 2009
[cited by applicant]
US 7872027B2
· Metallo et al.
· 2011
[cited by applicant]
US 8114422B2
· Fujii et al.
· 2012
[cited by applicant]
US 8188069B2
· Miller et al.
· 2012
[cited by applicant]
US 8188131B2
· Edge et al.
· 2012
[cited by applicant]
US 8226943B2
· Gurney et al.
· 2012
[cited by applicant]
US 8338482B2
· Chen et al.
· 2012
[cited by applicant]
US 20090258026A2
· Siebel et al.
· 2009
[cited by applicant]
US 20110251120A1
· Wang
· 2011
[cited by applicant]
US 20120107317A1
· Lau et al.
· 2012
[cited by applicant]
US 20210047618A1
· Clevers
· 2021
[cited by examiner]
EP 1949916
· 2011
[cited by applicant]
EP 2487156
· 2012
[cited by applicant]
WO WO1998028268
· 1998
[cited by applicant]
WO WO2002047671
· 2002
[cited by applicant]
WO WO2004090110A2
· 2004
[cited by applicant]
WO WO2004090110A3
· 2005
[cited by applicant]
WO WO2009005688A3
· 2009
[cited by applicant]
WO WO2009040423
· 2009
[cited by applicant]
WO WO2012080926
· 2012
[cited by applicant]
WO WO2014039908
· 2014
[cited by applicant]
WO WO2015168149
· 2015
[cited by applicant]
WO WO2017132530
· 2017
[cited by applicant]
WO WO2018172997
· 2018
[cited by applicant]
WO WO2022169881
· 2022
[cited by applicant]
Aggarwal et al., “Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice,” Clin. Cancer Res., Oct. 2005, 11(20):7…
[cited by applicant]
Ahmed et al., “Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2,” Dev. Cell., Feb. 2012, 22(2):377-390.
[cited by applicant]
Ashizawa et al., “Antitumor activity of a novel small molecule STAT3 inhibitor against a human lymphoma cell line with high STAT3 activation,” Int. J. Oncol., Feb. 2011, 38(5)1245-1252.
[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(10):e48704, 15 pages.
[cited by applicant]
CAS No. 1429639-50-8, “CZ415,” SelleckChem, retrieved on Feb. 18, 2022, retrieved from URL <https://www.selleckchem.com/products/CZ415.html>, 3 pages.
[cited by applicant]
CAS No. 154447-38-8, “LY 303511—CAS 154447-38-8—Calbiochem,” Sigma-Aldrich, retrieved on Apr. 4, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/mm/440203>, 6 pages.
[cited by applicant]
CAS No. 159351-69-6, “Everolimus,” Sigma-Aldrich, retrieved on Feb. 18, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/substance/everolimus95822159351696>, 2 pages.
[cited by applicant]
CAS No. 162635-04-3, “Temsirolimus,” Sigma-Aldrich, retrieved on Apr. 5, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/search/temsirolimus?focus=products&page=1&perpage=30&sort=relevance&term=temsirolimus…
[cited by applicant]
CAS No. 1660110-65-5, “SC-III3,” BOC Sciences, retrieved on Apr. 5, 2022, retrieved from URL <https://www.bocsci.com/sc-iii3-cas-1660110-65-5-item-475933.html>, 7 pages.
[cited by applicant]
CAS No. 1676893-24-5, “NSC781406,” retrieved on Apr. 4, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/targetmolchemicalsinc/ta9h9453348f?context=bbe>, 4 pages.
[cited by applicant]
CAS No. 1685280-21-0, “DMH-25,” MedKoo Biosciences Inc., retrieved on Feb. 18, 2022, retrieved from URL <https://www.medkoo.com/products/6774>, 2 pages.
[cited by applicant]
CAS No. 1927857-61-1, “PQR530,” Sigma-Aldrich, retrieved on Apr. 5, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/achemblock/advh97ebf28f?context=bbe>, 4 pages.
[cited by applicant]
CAS No. 326914-06-1, “MHY1485,” Sigma Aldrich, retrieved on Feb. 18, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/ambeedinc/ambh303c4b87?context=bbe>, 5 pages.
[cited by applicant]
CAS No. 53123-88-9, “Rapamycin,” Sigma-Aldrich, retrieved on Apr. 5, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/sial/37094>, 8 pages.
[cited by applicant]
CAS No. 572924-54-0, “Ridaforolimus,” Sigma-Aldrich, retrieved on Apr. 5, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/targetmolchemicalsinc/ta9h94533767?context=bbe>, 5 pages.
[cited by applicant]
CAS No. 57818-44-7, “ABTL-0812,” SelleckChem, retrieved on Feb. 18, 2022, retrieved from URL <https://www.selleckchem.com/products/abt1-0812.html>, 3 pages.
[cited by applicant]
CAS No. 6724-53-4, “Perhexiline maleate salt,” Sigma-Aldrich, retrieved on Apr. 5, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/search/6724-53-4?focus=products&page=1&perpage=30&sort=relevance&term=6724-…
[cited by applicant]
CAS No. 853910-61-9, “NVP-BBD130,” retrieved on Apr. 4, 2022, retrieved from URL <https://www.axonmedchem.com/product/1520>, 3 pages.
[cited by applicant]
CAS No. 914913-88-5, “Palomid 529,” retrieved on Apr. 4, 2022, retrieved from URL <https://www.sigmaaldrich.com/US/en/product/sigma/sm10801>, 6 pages.
[cited by applicant]
Chan et al., “Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia,” Blood, Jul. 2007, 110(1):278-286.
[cited by applicant]
Cheng et al., “Promotion of Ovarian Follicle Growth following mTOR Activation: Synergistic Effects of AKT Stimulators,” PLoS One, 2015, 10(2):e0117769, 9 pages.
[cited by applicant]
Choi et al., “Inhibitory effect of mTOR activator MHY1485 on autophagy: suppression of lysosomal fusion,” PLoS One, 2012, 7(8):e43418, 10 pages.
[cited by applicant]
Chung et al., “CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis,” J. Clin. Invest., Jun. 2012, 122(6):2257-2266.
[cited by applicant]
Churcher et al., “Design and Synthesis of Highly Potent Benzodiazepine γ-Secretase Inhibitors: Preparation of (2 S ,3 R )-3-(3,4-Difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy- N-((3 S )-1-methyl-2-oxo-5-phenyl-2,3-dihydr…
[cited by applicant]
Clausen et al., “In vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of 10074-G5, a novel small-molecule inhibitor of c-Myc/Max dimerization,” J. Pharmacol. Exp. Ther., Dec. 2010, 335(3):715-727.
[cited by applicant]
Daudet et al., “Notch Regulation of Progenitor Cell Behavior in Quiescent Regenerating Auditory Epithelium of Mature Birds,” Dev Biol, Feb. 2009, 326(1):86-100.
[cited by applicant]
Engelhard et al., “Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells,” J. Neurooncol., Apr. 1998, 37(2):97-108.
[cited by applicant]
Extended European Search Report in European Appln. No. 19744493.8, dated Oct. 19, 2021, 8 pages.
[cited by applicant]
Fauq et al., “A Multigram Chemical Synthesis of the y-Secretase Inhibitor LY411575 and its Diastereoisomers,” Bioorg Med Chem Lett, Oct. 2010, 17(22):6392-5.
[cited by applicant]
Fernandez et al., “Membrane Interactions of Antimicrobial Peptides from Australian Frogs,” Biochimica et Biophysica Acta (BBA)—Biomembranes, Aug. 2009, 1788(8):1630-1638.
[cited by applicant]
Fuwa et al., “Synthesis of Biotinylated Photoaffinity Probes Based on Arylsulfonamide γ-Secretase Inhibitors,” Bioorg Med Chem Lett, Aug. 2006, 16(16):4184-9.
[cited by applicant]
Ge & Ren, “mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism,” J Cell Mol Med, Mar. 2012, 16(3):615-626.
[cited by applicant]
Ge et al., “Identification of a novel MTOR activator and discovery of a competing endogenous RNA regulating autophagy in vascular endothelial cells,” Autophagy, Jun. 2014, 10(6):957-71.
[cited by applicant]
GenBank Accession No. NC_000010.11, “
[cited by applicant]
GenBank Accession No. NM_000435.2, “
[cited by applicant]
GenBank Accession No. NM_002467.4, “
[cited by applicant]
GenBank Accession No. NM_005172.1, “
[cited by applicant]
GenBank Accession No. NM_005378.4, “
[cited by applicant]
GenBank Accession No. NM_017617.3, “
[cited by applicant]
GenBank Accession No. NM_024408.3, “
[cited by applicant]
GenBank Accession No. NM_145178.3, “
[cited by applicant]
GenBank Accession No. NP_000426.2, “neurogenic locus notch homolog protein 3 precursor [
[cited by applicant]
GenBank Accession No. NP_002458.2, “myc proto-oncogene protein isoform 1 [
[cited by applicant]
GenBank Accession No. NP_004548.3, “neurogenic locus notch homolog protein 4 preproprotein [
[cited by applicant]
GenBank Accession No. NP_005163.1, “protein atonal homolog 1 [
[cited by applicant]
GenBank Accession No. NP_005369.2, “N-myc proto-oncogene protein isoform 1 [
[cited by applicant]
GenBank Accession No. NP_060087.3, “neurogenic locus notch homolog protein 1 preproprotein [
[cited by applicant]
GenBank Accession No. NP_077719.2, “neurogenic locus notch homolog protein 2 isoform 1 preproprotein [
[cited by applicant]
GenBank Accession No. NP_660161.1, “transcription factor ATOH7 [
[cited by applicant]
Genbank Accession No. AK021874.1, “
[cited by applicant]
GenBank Acession No. NC_000004.12, “
[cited by applicant]
GenBank Acession No. NM_004557.3, “
[cited by applicant]
Gera et al., “AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression,” J Biol Chem, Jan. 2004, 279(4)2737-2746.
[cited by applicant]
Gonzalez-Mariscal et al., “ZO-2, a tight junction protein involved in gene expression, proliferation, apoptosis, and cell size regulation,” Annals of the New York Academy of Sciences, Jun. 2017, 1397(1):35-53.
[cited by applicant]
Hartman et al., “Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear,” Proc Natl Acad Sci U S A, Sep. 2010, 107(36):15792-15797.
[cited by applicant]
Hu et al., “Induction of Differentiation of β-cell Leukemia Cell Lines JVM-2 and EHEB by Bryostatin 1,” Leuk Lymphoma, Jun. 1992, 10(1-2):135-42.
[cited by applicant]
Huang et al., “A Small-molecule c-Myc Inhibitor, 10058-F4, Induces Cell-cycle Arrest, Apoptosis, and Myeloid Differentiation of Human Acute Myeloid, Leukemia” Exp Hematol, Nov. 2006, 34(11):1480-9.
[cited by applicant]
Hurley et al., “Modulating the Functional Contributions of c-Myc to the Human Endothelial Cell Cyclic Strain Response,” J Vasc Res, Sep. 2009, 47(1):80-90.
[cited by applicant]
Imbimbo, “Therapeutic Potential of γ-Secretase Inhibitors and Modulators,” Curr Top Med Chem, 2008, 8(1):54-61.
[cited by applicant]
International Preliminary Report on Patentability in International Appln. No. PCT/US2019/015348, dated Jul. 28, 2020, 8 pages.
[cited by applicant]
International Preliminary Report on Patentability in International Appln. No. PCT/US2022/014952, mailed Aug. 17, 2023, 7 pages.
[cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/US2019/015348, dated Apr. 1, 2019, 9 pages.
[cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/US2022/14952, dated May 12, 2022, 10 pages.
[cited by applicant]
Ishikawa et al., “Opposing Functions of Fbxw7 in Keratinocyte Growth, Differentiation and Skin Tumorigenesis Mediated Through Negative Regulation of c-Myc and Notch,” Oncogene, 2013, 32:1921-32.
[cited by applicant]
Jadali et al., “Activation of P13K Signaling Prevents Aminoglycoside-Induced Hair Cell Death in the Murine Cochlea,” Biology Open, Jun. 2016, 5(6):698-708.
[cited by applicant]
Kelly et al., “Atoh1 Directs the Formation of Sensory Mosaics and Induces Cell Proliferation in the Postnatal Mammalian Cochlea In Vivo,” J Neurosci, May 2012, 32(19): 6699-6710.
[cited by applicant]
Kwan et al., “Development and Regeneration of Inner Ear,” Ann NY Acad Sci, Jul. 2009, 1170:28-33.
[cited by applicant]
Ladu et al., “E2F1 inhibits c-Myc-driven apoptosis via PIK3CNAkt/mTOR and COX-2 in a mouse model of human liver cancer,” Gastroenterology, Oct. 2008, 135:1322-1332.
[cited by applicant]
Lamming, “Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond,” Cold Spring Harb Perspect Med, 2016, 6:a025924: 15 pages.
[cited by applicant]
Lauber et al., “The Cooked Food Derived Carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine is a Potent Oestrogen: A Mechanistic Basis for its Tissue-specific Carcinogenicity,” Carcinogenesis, Dec. 2004, 25(12)…
[cited by applicant]
Lee et al., “Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration,” PLoS One, Jun. 2016, 11(6):e0157768, 21 pages.
[cited by applicant]
Leitmeyer et al., “Inhibition of mTOR by Rapamycin Results in Auditory Hair Cell Damage and Decreased Spiral Ganglion Neuron Outgrowth and Neurite Formation In Vitro,” BioMed Research International, Mar. 2015, 2015(2):1…
[cited by applicant]
Li and Doetzlhofer, “LIN28B/ let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling,” Proc Natl Acad Sci U S A, Sep. 2020, 117(36):22225-22236.
[cited by applicant]
Lin et al., “Small-molecule c-Myc Inhibitor, 10058-F4, Inhibits Proliferation, Downregulates Human Telomerase Reverse Transcriptase and Enhances Chemosensitivity in Human Hepatocellular Carcinoma Cells,” Anticancer Drug…
[cited by applicant]
Liu et al., “Age-dependent in vivo conversion of mouse cochlear pillar and Deiters' cells to immature hair cells by Atoh1 ectopic expression,” The Journal of Neuroscience, May 2012, 32(19):6600-6610.
[cited by applicant]
Mai et al., “Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides,” J Med Chem., May 2005, 48(9):3344-53.
[cited by applicant]
Masui et al., “mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc,” Cell Metab, Nov. 2013, 18(5):726-739.
[cited by applicant]
Matsushita et al., “Novel diagnosis and therapy for hepatoma targeting HBV-related carcinogenesis through alternative splicing of FIR (PUF60)/FIR[del]exon2,” Hepatoma Research, Sep. 2018, 4(61): 1-17.
[cited by applicant]
McEwan et al., “Cohesion is Required for Activation of MYC by Esterdiol,” PLoS One, Nov. 2012, 7(11):e49160, 14 pages.
[cited by applicant]
McLean et al., “Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells,” Cell Rep., Feb. 2017, 18(8):1917-1929.
[cited by applicant]
Mohamed et al., “Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration,” Cell, Mar. 2018, 173(1):104-116.e12, 26 pages.
[cited by applicant]
Montcouquiol et al., “Intracellular Signals That Control Cell Proliferation in Mammalian Balance Epithelia: Key Roles for Phosphatidylinositol-3 Kinases, Mammalian Target of Rapamycin, and S6 Kinases in Preference to Ca…
[cited by applicant]
Moon et al., “WNT and β-catenin Signalling: Diseases and Therapies,” Nat Rev Genet, Sep. 2004, 5(9):689-699.
[cited by applicant]
Mori et al., “Chemoprevention by Naturally Occurring and Synthetic Agents in Oral, Liver, and Large Bowel Carcinogenesis,” J Cell Biochem Suppl, 1997, 27:35-41.
[cited by applicant]
Ni et al., “Extensive Supporting Cell Proliferation and Mitotic Hair Cell Generation by In Vivo Genetic Reprogramming in the Neonatal Mouse Cochlea,” J Neurosci., Aug. 2016, 36(33):8734-45.
[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]
Page et al., “Small Molecule STAT5-SH2 Domain Inhibitors Exhibit Potent Antileukemia Activity,” J Med Chem, Feb. 2012, 55(3):1047-1055.
[cited by applicant]
Pan et al., “Notch Signaling is Required for the Generation of Hair Cells and Supporting Cells in the Mammalian Inner Ear,” Proc Natl Acad Sci USA, Aug. 2010, 107(36):15798-15803.
[cited by applicant]
Park et al., “Inhibition of AP-1 Transcription Activator Induces Myc-Dependent Apoptosis in HL 60 Cells,” J Cell Biochem, Apr. 2004, 91(5):973-986.
[cited by applicant]
Purow, “Notch Inhibition as a Promising New Approach to Cancer Therapy,” Adv Exp Med Biol, 2012, 727:305-19.
[cited by applicant]
Ramachandran and Ignacimuthu, “RNA interference—a silent but an efficient therapeutic tool,” Appl Biochem Biotechnol., Mar. 2013, 169(6):1774-89.
[cited by applicant]
Sai et al., “Induction of Cell-cycle Arrest and Apoptosis in Glioblastoma Stem-like Cells by WP1193, a Novel Small Molecule Inhibitor of the JAK2/STAT3 Pathway,” J Neurooncol, May 2012, 107(3):487-501.
[cited by applicant]
Samon et al., “Preclinical Analysis of the γ-Secretase Inhibitor PF-03084014 in Combination with Glucocorticoids in T-Cell Acute Lymphoblastic Leukemia,” Mol Cancer Ther, Jul. 2012, 11(7):1565-75.
[cited by applicant]
Shi et al., “Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors,” Proc Natl Acad Sci U S A, Aug. 2013, 110(34):13851-6.
[cited by applicant]
Shih and Wang, “Notch Signaling, γ-Secretase Inhibitors, and Cancer Therapy,” Cancer Res, Mar. 2007, 67(5):1879-82.
[cited by applicant]
Shu et al., “Renewed proliferation in adult mouse cochlea and regeneration of hair cells,” Nature Communications, 2019, 10:5530, 15 pages.
[cited by applicant]
Smetanina et al., “Ortho-aminoazotoluene Activates Mouse Constitutive Androstane Receptor (mCAR) and Increases Expression of mCAR Target Genes,” Toxicol Appl Pharmacol, Aug. 2011, 255(1):76-85.
[cited by applicant]
Takebayashi et al., “Multiple Roles of Notch Signaling in Cochlear Development,” Dev Biol, Jul. 2007, 307(1):165-78.
[cited by applicant]
UniProt Accession No. P60484, “RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN; AltName: Full=Mutated in multiple advanced cancers 1; AltName: Full=Phos…
[cited by applicant]
Weihofen et al., “Identification of Signal Peptide Peptidase, a Presenilin-type Aspartic Protease,” Science, Jun. 2002, 296(5576):2215-8.
[cited by applicant]
Yao et al., “Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas,” Nature, Aug. 2018, 560(7719):484-488, 17 pages.
[cited by applicant]
Zhang et al., “Orally Bioavailable Small-molecule Inhibitor of Transcription Factor STAT3 Regresses Human Breast and Lung Cancer Xenografts,” Proc Natl Acad Sci USA, Jun. 2012, 109(24):9623-8.
[cited by applicant]
Zhang et al., “PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications,” Stem Cell Reports, May 2017, 8:1256-1269.
[cited by applicant]
Zhao et al., “MHY1485 activates mTOR and protects osteoblasts from dexamethasone,” Biochemical and biophysical research communications, 2016, 481(3-4):212-218.
[cited by applicant]