Granted Patent
B2
US 12,285,427 · App. 18/215,731 · Granted Apr 29, 2025
Treatment of a senescence-associated ocular disease or disorder using a Bcl-xL selective inhibitor
Inventors:
Remi-Martin Laberge (South San Francisco, CA); Judith Campisi (Berkeley, CA); Marco Demaria (San Francisco, CA); Bennett G. Childs (Rochester, MN); Jan M. A. Van Deursen (Rochester, MN); Nathaniel David (South San Francisco, CA); Alain Philippe Vasserot (South San Francisco, CA)
Assignees:
Unity Biotechnology, Inc.; Mayo Foundation for Medical Education and Research; Buck Institute for Research on Aging
A61K31/496A61K9/0048A61K9/0073A61K31/404A61K31/4178A61K31/428A61K31/4375A61K31/495A61K31/5377A61K31/728A61K45/06A61K47/36A61P9/10A61P11/00A61P25/16A61P27/02C12N5/0081A61P25/28C12N2501/999C12N2503/02C12Q1/485
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Abstract
This invention establishes a new paradigm for treatment of Parkinson's disease (PD) by eliminating senescent cells that reside in or around the site of the disease pathophysiology. Exposure of test subjects to the herbicide paraquat (PQ) increases the risk for developing Parkinson's disease. The data in this disclosure show that PQ induces a senescence arrest and SASP in astrocytes, in culture and in vivo in mice, and senescent cell markers were present in astrocytes in midbrain tissue from PD patients. In a transgenic mouse model, senescent cell ablation protected against PQ-induced PD-like neuropathology. Removal of senescent cells from affected sites using small molecule agents that specifically target senescent cells can help prevent or ameliorate signs and symptoms of the disease.
Claims (4)
1. A method for treating a senescence-associated ocular disease or disorder in an eye of a subject in need thereof, the method comprising administering an inhibitor of a Bcl-2 anti-apoptotic protein family member, wherein the inhibitor is WEHI-539 or A-1155463, and wherein the inhibitor selectively eliminates senescent cells in the eye of the subject.
2. The method of claim 1 , wherein the senescence-associated ocular disease or disorder is an age-related macular degeneration, cataracts, glaucoma, vision loss, or presbyopia.
3. The method of claim 1 , wherein the inhibitor is WEHI-539.
4. The method of claim 1 , wherein the inhibitor is A-1155463.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 7, 2024
From: LABERGE, REMI-MARTIN; CAMPISI, JUDITH; DAVALOS, ALBERT; DEMARIA, MARCO
To: BUCK INSTITUTE FOR RESEARCH ON AGING
Reel/Frame 067658/0795 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 7, 2024
From: BAKER, DARREN J.; CHILDS, BENNETT G.; KIRKLAND, JAMES L.; TCHKONIA, TAMAR; VAN DEURSEN, JAN M.A.
To: MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH
Reel/Frame 067658/0801 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 7, 2024
From: DAVID, NATHANIEL; VASSEROT, ALAIN PHILIPPE
To: UNITY BIOTECHNOLOGY, INC.
Reel/Frame 067658/0807 →
Continuity (16)
Continuation
15114762
Provisional Application
62061627
· Oct 8, 2014
Provisional Application
62061629
· Oct 8, 2014
Provisional Application
62057828
· Sep 30, 2014
Provisional Application
62057825
· Sep 30, 2014
Provisional Application
62057820
· Sep 30, 2014
Provisional Application
62044664
· Sep 2, 2014
Provisional Application
62042708
· Aug 27, 2014
Provisional Application
62002709
· May 23, 2014
Provisional Application
61979911
· Apr 15, 2014
Provisional Application
61932704
· Jan 28, 2014
Provisional Application
61932711
· Jan 28, 2014
References Cited (227)
US 5856171A
· Korsmeyer
· 1999
[cited by applicant]
US 6617346B1
· Kong et al.
· 2003
[cited by applicant]
US 6734302B2
· Kong et al.
· 2004
[cited by applicant]
US 7482134B2
· Jang et al.
· 2009
[cited by applicant]
US 7705007B2
· Fotouhi et al.
· 2010
[cited by applicant]
US 7767684B2
· Bruncko et al.
· 2010
[cited by applicant]
US 7842681B2
· Elmore et al.
· 2010
[cited by applicant]
US 7851626B2
· Ding et al.
· 2010
[cited by applicant]
US 7893278B2
· Haley et al.
· 2011
[cited by applicant]
US 8114893B2
· Baell et al.
· 2012
[cited by applicant]
US 8168645B2
· Baell et al.
· 2012
[cited by applicant]
US 8168784B2
· Franczyk, II et al.
· 2012
[cited by applicant]
US 8343967B2
· Ding et al.
· 2013
[cited by applicant]
US 8426422B2
· Hexamer et al.
· 2013
[cited by applicant]
US 8563735B2
· Bruncko et al.
· 2013
[cited by applicant]
US 8586754B2
· Bruncko et al.
· 2013
[cited by applicant]
US 8691184B2
· Wang et al.
· 2014
[cited by applicant]
US 9018381B2
· Diebold et al.
· 2015
[cited by applicant]
US 9248140B2
· Diebold et al.
· 2016
[cited by applicant]
US 9266860B2
· Guy et al.
· 2016
[cited by applicant]
US 9360471B2
· Qi
· 2016
[cited by applicant]
US 9527847B2
· Palombella et al.
· 2016
[cited by applicant]
US 9630990B2
· Shetty et al.
· 2017
[cited by applicant]
US 9849128B2
· Laberge et al.
· 2017
[cited by applicant]
US 9855266B2
· Laberge et al.
· 2018
[cited by applicant]
US 9980962B2
· Laberge et al.
· 2018
[cited by applicant]
US 20020054915A1
· Goldenheim et al.
· 2002
[cited by applicant]
US 20020197602A1
· Burmer et al.
· 2002
[cited by applicant]
US 20030086916A1
· Goligorsky et al.
· 2003
[cited by applicant]
US 20040242545A1
· Otsuka et al.
· 2004
[cited by applicant]
US 20050181076A1
· Ziegler
· 2005
[cited by applicant]
US 20060122150A1
· Argentieri et al.
· 2006
[cited by applicant]
US 20080221132A1
· Cai et al.
· 2008
[cited by applicant]
US 20080234362A1
· Chandler
· 2008
[cited by applicant]
US 20100016218A1
· Lichter et al.
· 2010
[cited by applicant]
US 20100087436A1
· Bardwell et al.
· 2010
[cited by applicant]
US 20100292200A1
· Kile et al.
· 2010
[cited by applicant]
US 20100310504A1
· Lowe et al.
· 2010
[cited by applicant]
US 20110028437A1
· Robbins et al.
· 2011
[cited by applicant]
US 20110212909A1
· Wen et al.
· 2011
[cited by applicant]
US 20120046333A1
· Hardie et al.
· 2012
[cited by applicant]
US 20120108590A1
· Birtalan et al.
· 2012
[cited by applicant]
US 20120129853A1
· Elmore et al.
· 2012
[cited by applicant]
US 20120156134A1
· Squires
· 2012
[cited by applicant]
US 20120277210A1
· Catron et al.
· 2012
[cited by applicant]
US 20120283269A1
· Blagosklonny et al.
· 2012
[cited by applicant]
US 20130149314A1
· Bullerdiek et al.
· 2013
[cited by applicant]
US 20130225603A1
· Chavala et al.
· 2013
[cited by applicant]
US 20130287763A1
· Sathyanarayanan et al.
· 2013
[cited by applicant]
US 20130302283A1
· Kihm
· 2013
[cited by applicant]
US 20140017341A1
· Gourlaouen
· 2014
[cited by applicant]
US 20140220111A1
· Hayes et al.
· 2014
[cited by applicant]
US 20140272947A1
· Zhang et al.
· 2014
[cited by applicant]
US 20140275082A1
· Tao et al.
· 2014
[cited by applicant]
US 20140328893A1
· Adnot
· 2014
[cited by applicant]
US 20150051215A1
· Wooster et al.
· 2015
[cited by applicant]
US 20150126573A1
· Boczkowski et al.
· 2015
[cited by applicant]
US 20150140036A1
· Mannick et al.
· 2015
[cited by applicant]
US 20150231136A1
· Chavala et al.
· 2015
[cited by applicant]
US 20160022720A1
· Jordan
· 2016
[cited by applicant]
US 20160122758A1
· Krizhanovsky et al.
· 2016
[cited by applicant]
US 20170196858A1
· Laberge et al.
· 2017
[cited by applicant]
EP 3139942
· 2017
[cited by applicant]
KR 20120118596A
· 2012
[cited by applicant]
KR 20130139512A
· 2013
[cited by applicant]
WO WO2003028443A1
· 2003
[cited by applicant]
WO WO2003051359A1
· 2003
[cited by applicant]
WO WO2006018632A2
· 2006
[cited by applicant]
WO WO2006039704A2
· 2006
[cited by applicant]
WO WO2008113131A1
· 2008
[cited by applicant]
WO WO2008125487A1
· 2008
[cited by applicant]
WO WO2009039553A1
· 2009
[cited by applicant]
WO WO2009105234A2
· 2009
[cited by applicant]
WO WO2010080478A1
· 2010
[cited by applicant]
WO WO2010148447A1
· 2010
[cited by applicant]
WO WO2011068560A1
· 2011
[cited by applicant]
WO WO2011083150
· 2011
[cited by applicant]
WO WO2014186878A1
· 2014
[cited by applicant]
WO WO2015051252A1
· 2015
[cited by applicant]
WO WO2015066442A1
· 2015
[cited by applicant]
WO WO2015116735A1
· 2015
[cited by applicant]
WO WO2015116740A1
· 2015
[cited by applicant]
WO WO2015181526A1
· 2015
[cited by applicant]
Anderson et al., “Why is Osteoarthritis an Age-Related Disease?”, Best Pract Res Clin Rheumatol., vol. 24, No. 1, Feb. 2010, 15 pages.
[cited by applicant]
Arya et al., “Nutlin-3, the Small-Molecule Inhibitor of MDM2, Promotes Senescence and Radiosensitises Laryngeal Carcinoma Cells Harbouring Wild-Type p53”, Br J Cancer, vol. 103, No. 2, Jul. 13, 2010, pp. 186-195, doi: 1…
[cited by applicant]
Axanova et al., “1,25-Dihydroxyvitamin D3 and PI3K/AKT Inhibitors Synergistically Inhibit Growth and Induce Senescence in Prostate Cancer Cells”, Prostate, vol. 70, No. 15, Nov. 1, 2010, pp. 1658-1671.
[cited by applicant]
Bajwa et al, “Inhibitors of the Anti-Apoptotic Bcl-2 Proteins: A Patent Review”, Expert Opin Ther Pat., vol. 22, No. 1, Jan. 2012, pp. 37-55, doi: 10.1517/13543776.2012.644274, Epub Dec. 23, 2011.
[cited by applicant]
Baker et al., “Clearance of p16Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders”, Nature, vol. 479, No. 7372, 2011, pp. 232-236.
[cited by applicant]
Barak et al., “Mdm2 Expression is Induced by Wild Type p53 Activity”, EMBO J., vol. 12, No. 2, Feb. 1993, pp. 461-468.
[cited by applicant]
Berenbaum (2013) “Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!)”, Osteoarthritis and Cartilage 21:16-21.
[cited by applicant]
Brenkman et al., “Mdm2 Induces Mono-Ubiquitination of FOX04”, PLoS One, vol. 3, No. 7, Jul. 30, 2008, e2819. doi: 10.1371/journal.pone.0002819.
[cited by applicant]
Campisi et al., “Cell Senescence: Role in Aging and Age-Related Diseases”, Interdiscip Top Gerontol., vol. 39, 2014, pp. 45-61, doi: 10.1159/000358899, Epub May 13, 2014.
[cited by applicant]
Campisi, J., “Cellular Senescence as a Tumor-Suppressor Mechanism”, Trends Cell Biol., vol. 11, No. 11, Nov. 2001, pp. S27-S31.
[cited by applicant]
Campisi, J., “Cellular Senescence: Putting the Paradoxes in Perspective”, Curr Opin Genet Dev., vol. 21, No. 1, Feb. 2011, pp. 107-112, doi: 10.1016/j.gde.2010.10.005, Epub Nov. 17, 2010.
[cited by applicant]
Campisi, J., “Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors”, Cell, vol. 120, No. 4, Feb. 25, 2005, pp. 513-522.
[cited by applicant]
Caruso et al., “Apoptotic-Like Tumor Cells and Apoptotic Neutrophils in Mitochondrion-Rich Gastric Adenocarcinomas: A Comparative Study with Light and Electron Microscopy Between these Two Forms of Cell Death”, Rare Tum…
[cited by applicant]
Chang et al., “Clearance of Senescent Cells by ABT263 Rejuvenates Aged Hematopoietic Stem Cells in Mice”, Nat Med., vol. 22, Dec. 14, 2015, pp. 78-83, doi: 10.1038/nm.4010.
[cited by applicant]
Chappell et al., “Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting these Pathways in Human Health”, Oncotarget., vol. 2, No. 3, Mar. 2011, pp. 135-164.
[cited by applicant]
Co-pending U.S. Application: David et al., “Treatment of Joint Pain”, U.S. Appl. No. 15/481,129, filed Apr. 6, 2017.
[cited by applicant]
Co-pending U.S. Application: Remi-Martin Laberge et al., “Treatment of Ophthalmic Conditions by Selectively Removing Senescent Cells from the Eye”, U.S. Appl. No. 15/827,539, filed Nov. 30, 2017.
[cited by applicant]
Co-Pending U.S. Application: Laberge et al., “Treating Pulmonary Conditions by Selectively Removing Senescent Cells from the Lung using an Intermittent Dosing Regimen”, U.S. Appl. No. 15/955,542, filed Apr. 17, 2018.
[cited by applicant]
Co-Pending U.S. Application: Laberge et al. “Removing Senescent Cells from a Mixed Cell Population or Tissue using a Phosphoinositide 3-Kinase (Pi3k) Inhibitor”, U.S. Appl. No. 15/981,696, filed May 16, 2018.
[cited by applicant]
Co-Pending U.S. Application: Laberge et al., “Use of Sulfonamide Inhibitors of Bcl-2 and Bel-XI To Treat Ophthalmic Disease By Selectively Removing Senescent Cells” U.S. Appl. No. 16/054,667, filed Aug. 3, 2018, pp. 1-2…
[cited by applicant]
Coppe et al., “A Human-Like Senescence-Associated Secretory Phenotype is Conserved in Mouse Cells Dependent on Physiological Oxygen”, PLoS One, vol. 5, 2010, e9188.
[cited by applicant]
Coppe et al., “Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor”, PLoS Biol., vol. 6, No. 12, Dec. 2, 2008, pp. 2853-2868, doi: 10.1371/journal…
[cited by applicant]
Dienstmann et al., “Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors”, Mol Cancer Ther., vol. 13, No. 5, May 2014, pp. 1021-1031, Epub Apr. 18, 2014.
[cited by applicant]
Doroshevskaya et al., “Apoptosis Regulator Proteins: Basis for the Development of Innovation Strategies for the Treatment of Rheumatoid Arthritis in Patients of Different Age”. Bulletin of Experimental Biology and Medic…
[cited by applicant]
Efeyan et al., “Induction of p53-dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin”, Cancer Res., vol. 67, No. 15, Aug. 1, 2007, pp. 7350-7357.
[cited by applicant]
Laberge et al., “Methods and Compositions for Killing Senescent Cells and for Treating Senescence-Associated Diseases and Disorders”, Extended European Search Report and Search Opinion received for European Application …
[cited by applicant]
Laberge et al., “Unit Dose of a Cis-Imidazoline for Treating an Osteoarthritic Joint by Removing Senescent Cells”, First Action Interview Pilot Program Pre-Interview Communication received for U.S. Appl. No. 15/455,575,…
[cited by applicant]
Freund et al., p38MAPK is a Novel DNA Damage Response-Independent Regulator of the Senescence-Associated Secretory Phenotype, EMBO J., vol. 30, No. 8, Apr. 20, 2011, pp. 1536-1548, doi: 10.1038/emboj.2011.69, Epub Mar. …
[cited by applicant]
Gagarina et al., “SirT1 Enhances Survival of Human Osteoarthritic Chondrocytes by Repressing Protein Tyrosine Phosphatase 18 and Activating the Insulin-Like Growth Factor Receptor Pathway”, Arthritis Rheum., vol. 62, No…
[cited by applicant]
Gannon et al., “Mdm2-p53 Signaling Regulates Epidermal Stem Cell Senescence and Premature Aging Phenotypes in Mouse Skin”. Developmental Biology, vol. 353, 2011, pp. 1-9.
[cited by applicant]
Golstein et al., “Cell Death by Necrosis: Towards a Molecular Definition”, Trends in Biochemical Sciences, vol. 32, No. 1, Jan. 2007, pp. 37-43.
[cited by applicant]
Guan et al. “Imidazoline Derivatives: A Patent Review (2006-present)”, Expert Opin Ther Pat., vol. 22, No. 11, Nov. 2012, pp. 1353-1365, doi: 10.1517/13543776.2012.727397, Epub Sep. 24, 2012.
[cited by applicant]
Hashimoto et al. “Role of p53 in Human Chondrocyte Apoptosis in Response to Shear Strain”, Arthritis Rheum., vol. 60, No. 8, Aug. 2009, pp. 2340-2349.
[cited by applicant]
Haupt et al., “Mdm2 Promotes the Rapid Degradation of p53”, Nature, vol. 387, No. 6630, May 15, 1997, pp. 296-299.
[cited by applicant]
Holford et al., “Phannacokinetics and Phannacodynamics: Dose Selection & the Time Course of Drug Action”, In: Katzung B.G., ed. Basic & Clinical Pharmacology (7th ed.), Appleton & Lange, Stamford, CT, 1998, pp. 34-49.
[cited by applicant]
Honda et al., “Oncoprotein MDM2 is a Ubiquitin Ligase E3 for Tumor Suppressor p53”, FEBS Lett., vol. 420, No. 1, Dec. 22, 1997, pp. 25-27.
[cited by applicant]
Huang et al. “Reduced Transcriptional Activity in the p53 Pathway of Senescent Cells Revealed by the MDM2 Antagonist Nutlin-3”, Aging (Albany NY), vol. 1, No. 10, Oct. 2009, pp. 845-854, doi: 10.18632/aging.100091, Epub…
[cited by applicant]
Ianitti et al., “Intra-Articular Injections for the Treatment of Osteoarthritis: Focus on the Clinical Use of Hyaluronic Acid”, Drugs R D., vol. 11, No. 1, 2011, pp. 13-27.
[cited by applicant]
Kirkland et al. “Methods and Combinations for Killing Senescent Cells and for Treating Senescence-Associated Diseases and Disorders”, International Preliminary Report on Patentability received for PCT Patent Application…
[cited by applicant]
Laberge et al., “Methods and Compositions for Killing Senescent Cells and for Treating Senescence-Associated Diseases and Disorders”, International Preliminary Report on Patentability received for PCT Patent Application…
[cited by applicant]
Jakubsick et. al., “Human Pulmonary Fibroblasts Exhibit Altered Interleukin-4 and Interleukin-13 Receptor Subunit Expression in Idiopathic Interstitial Pneumonia”, Am J Pathol., vol. 164, No. 6, Jun. 2004, pp. 1989-2001.
[cited by applicant]
Jeon et al., “Local Clearance of Senescent Cells Attenuates the Development of Post-Traumatic Osteoarthritis and Creates a Pro-Regenerative Environment”, Nat Med., vol. 23, No. 6, Jun. 2017, pp. 775-781, doi: 10.1038/nm…
[cited by applicant]
Juven et al., “Wild Type p53 can Mediate Sequence-Specific Transactivation of an Internal Promoter within the Mdm2 Gene”, Oncogene, vol. 8, No. 12, Dec. 1993, pp. 3411-3416.
[cited by applicant]
Kegel, Magdalena, “Cancer Drug Candidate to be Tested on Lung Fibrosis in Phase 1 Clinical Trial”, Pulmonary Fribrosis News, May 2, 2016, pp. 1-2.
[cited by applicant]
Kerr et al., “Apoptosis: A Basic Biological Phenomenon with Wide-Ranging Implications in Tissue Kinetics”, Br J Cancer, vol. 26, No. 4, Aug. 1972, pp. 239-257.
[cited by applicant]
Kroemer et al., “Classification of Cell Death: Recommendations of the Nomenclature Committee on Cell Death 2009”, Cell Death Differ., vol. 16, No. 1, Jan. 2009, pp. 3-11.
[cited by applicant]
Kubbutat et al., “Regulation of p53 Stability by Mdm2”, Nature, vol. 387, No. 6630, May 15, 1997, pp. 299-303.
[cited by applicant]
Laberge et al., “Glucocorticoids Suppress Selected Components of the Senescence-Associated Secretory Phenotype”, Aging Cell, vol. 11, No. 4, 2012, pp. 569-578.
[cited by applicant]
Laberge et al., “Mitochondrial DNA Damage Induces Apoptosis in Senescent Cells”, Cell Death Dis., vol. 4, Jul. 18, 2013, e727, doi: 10.1038/cddis.2013.199.
[cited by applicant]
Lahav, Galit, “Oscillations by the p53-Mdm2 Feedback Loop”, Adv Exp Med Biol., vol. 641, 2008, pp. 28-38.
[cited by applicant]
Le Cras et al., “Inhibition of PI3K by PX-866 Prevents Transforming Growth Factor-α-Induced Pulmonary Fibrosis”, Am J Pathol., vol. 176, No. 2, Feb. 2010, pp. 679-686, Epub Dec. 30, 2009.
[cited by applicant]
Leist et al., “Four Deaths and A Funeral: From Caspases to Alternative Mechanisms”, Nat Rev Mol Cell Biol., vol. 2, No. 8, Aug. 2001, pp. 589-598.
[cited by applicant]
Lessene et al., “Structure-Guided Design of a Selective BCL-X(L) Inhibitor”, Nat Chem Biol., vol. 9, No. 6, Jun. 2013, pp. 390-397.
[cited by applicant]
Liu et al., “The PI3K-Akt Pathway Inhibits Senescence and Promotes Self-Renewal of Human Skin-derived Precursors in Vitro”, Aging Cell, vol. 10, No. 4, Aug. 2011, pp. 661-674, Epub May 3, 2011.
[cited by applicant]
Loeser, Richard F., “Aging and Osteoarthritis: The Role of Chondrocyte Senescence and Aging Changes in the Cartilage Matrix”, Osteoarthritis Cartilage, vol. 17, No. 8, Aug. 2009, pp. 971-979, doi: 10.1016/j.joca.2009.03…
[cited by applicant]
Manfredi, James, “The Mdm2-p53 Relationship Evolves: Mdm2 Swings Both Ways as an Oncogene and a Tumor Suppressor”, Genes Dev., vol. 24, No. 15, Aug. 1, 2010, pp. 1580-1589, doi: 10.1101/gad.1941710.
[cited by applicant]
Markman et al., “Targeting the PI3K/Akt/mTOR Pathway-Beyond Rapalogs”, Oncotarget, vol. 1, No. 7, Nov. 2010, pp. 530-543.
[cited by applicant]
Martin et al., “Chondrocyte Senescence, Joint Loading and Osteoarthritis”, Clin Orthop Relat Res., 427 Suppl, Oct. 2004, pp. S96-S103.
[cited by applicant]
Naylor et al., (2013) “Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases”, Clin Pharmacol Ther. 93(1): 105-116.
[cited by applicant]
Momand et al. “The Mdm-2 Oncogene Product Forms a Complex with the p53 Protein and Inhibits p53-Mediated Transactivation”, Cell, vol. 69, No. 7, Jun. 26, 1992, pp. 1237-1245.
[cited by applicant]
No Author. Form S-1 Registration Statement as Filed with the Securities and Exchange Commission on Apr. 23, 2018, pp. 1-243.
[cited by applicant]
No Author. Glossary of medical education terms, institute of International Medical Education. pp. 1-23. http://www.iime.ogr/glossary.htm [Accessed Mar. 2013].
[cited by applicant]
Laberge et al., “Unit Dose of a Cis-Imidazoline for Treating an Osteoarthritic Joint by Removing Senescent Cells”, Notice of Allowance and corresponding allowed claims received for U.S. Appl. No. 15/455,575, dated Aug. …
[cited by applicant]
Laberge et al., “Treatment for Osteoarthritis by Intra-Articular Administration of a Cis-Imidazoline”, Notice of Allowance and corresponding allowed claims received in U.S. Appl. No. 15/467,129, dated Aug. 3, 2017.
[cited by applicant]
David, Nathaniel, “Chemical Entities that Kill Senescent Cells for Use in Treating Age-Related Disease”, Office Action received for U.S. Appl. No. 15/069,769, dated May 17, 2017.
[cited by applicant]
Laberge et al., “Treatment for Osteoarthritis by Intra-Articular Administration of a Cis-Imidazoline”, Office Communication received for U.S. Appl. No. 15/467,129, dated Jul. 21, 2017.
[cited by applicant]
Laberge et al., “Treatment for Osteoarthritis in a Joint by Administering a means for Inhibiting Mdm2” Office Communication received for U.S. Appl. No. 15/114,762, filed Sep. 14, 2017.
[cited by applicant]
David et al., “Treatment of Joint Pain”, Office Communication received for U.S. Appl. No. 15/481,129, dated Sep. 27, 2017.
[cited by applicant]
Oliner et al., “Oncoprotein MDM2 Conceals the Activation Domain of Tumour Suppressor p53”, Nature, vol. 362, No. 6423, Apr. 29, 1993, pp. 857-860.
[cited by applicant]
Perry et al., “The Mdm-2 Gene is Induced in Response to UV light in a p53-Dependent Manner”, Proc Natl Acad Sci USA., vol. 90, No. 24, Dec. 15, 1993, pp. 11623-11627.
[cited by applicant]
Prieur et al., “Cellular Senescence in Vivo: A Barrier to Tumorigenesis”, Curr Opin Cell Biol., vol. 20, No. 2, Apr. 2008, pp. 150-155, doi: 10.1016/j.ceb.2008.01.007, Epub Mar. 18, 2008.
[cited by applicant]
Rodier et al., “Persistent DNA Damage Signalling Triggers Senescence-Associated Inflammatory Cytokine Secretion”, Nat Cell Biol., vol. 11, No. 8, Aug. 2009, pp. 973-979, doi; 10.1038/ncb1909, Epub Jul. 13, 2009.
[cited by applicant]
Saczewski et al., “Imidazoline Scaffold in Medicinal Chemistry: A Patent Review (2012-2015)”, Expert Opin Ther Pat., vol. 26. No. 9, Jul. 20, 2016, pp. 1031-1048.
[cited by applicant]
Shangary et al. “Temporal Activation of p53 by a Specific MDM2 Inhibitor is Selectively Toxic to Tumors and Leads to Complete Tumor Growth Inhibition”, Proc Natl Acad Sci USA, vol. 105, No. 10, Mar. 11, 2008, pp. 3933-3…
[cited by applicant]
Taranto et al., “Detection of the p53 Regulator Murine Double-Minute Protein 2 in Rheumatoid Arthritis”, J Rheumatol., vol. 32, No. 3. Mar. 2005, pp. 424-429.
[cited by applicant]
Thomasova et al., “p53-Independent Roles of MDM2 in NF-κB Signaling: Implications for Cancer Therapy, Wound Healing, and Autoimmune Diseases”, Neoplasia, vol. 14, No. 12. Dec. 2012, pp. 1097-1101.
[cited by applicant]
Tovar et al., “MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models”, Cancer Res., vol. 73, No. 8, Apr. 15, 2013, pp. 2587-2597, doi: 10.1158/0008-5472.CA…
[cited by applicant]
Kirkland et al., “Killing Senescent Cells and Treating Senescence-Associated Conditions using a SRC Inhibitor and a Flavonoid”, Non-Final Office Action received for U.S. Appl. No. 15/113,723, dated Jul. 26, 2018.
[cited by applicant]
Laberge et al., “Methods and Compositions for Selectively Removing Senescent Cells from a Mixed Cell Population or Tissue by Inhibiting the P53 Negative Regulator Mouse Double Minute 2 Homolog (Mdm2)”, Non-Final Office …
[cited by applicant]
Laberge et al., “Methods and Compositions for Selectively Removing Senescent Cells from a Mixed Cell Population or Tissue by Inhibiting the P53 Negative Regulator Mouse Double Minute 2 Homolog (Mdm2)”, Non-Final Office …
[cited by applicant]
Laberge et al., “A Method of Optimizing Conditions for Selectively Removing a Plurality of Senescent Cells from a Tissue or a Mixed Cell Population”, First Action Interview Office Action Summary received for U.S. Appl. …
[cited by applicant]
Laberge et al., “A Method of Optimizing Conditions for Selectively Removing a Plurality of Senescent Cells from a Tissue or a Mixed Cell Population”, First Action Interview Pilot Program, Pre-Interview Communication rec…
[cited by applicant]
David et al., “Treatment of Joint Pain”, First Action Interview received for U.S. Appl. No. 15/481,129, dated Nov. 20, 2017.
[cited by applicant]
Laberge et al., “Treating Pulmonary Conditions by Selectively Removing Senescent Cells from the Lung using an Intermittent Dosing Regimen”, First Action Interview Pilot Program Pre-Interview Communication received for U…
[cited by applicant]
UAMS News Bureau, “UAMS Research Findings Show Radiation, Aging Effects Can Be Cleared with Drug”, Findings Published in Nature Medicine, Dec. 14, 2015, 2 pages, Available at <www.uamshealth.com/news>.
[cited by applicant]
Uraoka et al., “Loss of bcl-2 during the Senescence Exacerbates the Impaired Angiogenic Functions in Endothelial Cells by Deteriorating the Mitochondrial Redox State”, Hypertension, vol. 58, No. 2, Aug. 2011, pp. 254-26…
[cited by applicant]
Van Deursen, Jan M., “The Role of Senescent Cells in Ageing”, Nature, vol. 509, No. 7501, May 22, 2014, pp. 439-446, doi: 10.1038/nature13193.
[cited by applicant]
Vassilev et al., “In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2”, Science, vol. 303, No. 5659, Feb. 6, 2004, pp. 844-848, Epub Jan. 2, 2004.
[cited by applicant]
Wang, E., “Senescent Human Fibroblasts Resist Programmed Cell Death, and Failure to Suppress bcl2 is Involved”, Cancer Res., vol. 55, No. 11, Jun. 1, 1995, pp. 2284-2292.
[cited by applicant]
Wilson C., “Sweep Away Senile Cells”, Life Extension Magazine, Mar. 2015, pp. 1-17.
[cited by applicant]
Zauli et al., “Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity in both p53 Wild-Type and p53 Mutated B Chronic Lymphocytic Leukemias by Inhibiting the Akt Pathway”, Clin Cancer Res., vol. 17, No. 4, Feb.…
[cited by applicant]
Zhang et al., “MDM2 Promotes Rheumatoid Arthritis via Activation of MAPK and NF-κB”, Int Immunopharmacol., vol. 30, Dec. 2, 2015, pp. 69-73.
[cited by applicant]
Zhao et al., “Small Molecule Inhibitors of MDM2-p53 and MDMX-p53 interactions as New Cancer Therapeutics”, BioDiscovery, vol. 8, No. 4, 2013, 15 pages.
[cited by applicant]
Zhu et al., “Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors”, Aging Cell, vol. 15, No. 3, Jun. 2016, pp. 428-435, Epub Mar. 18, 2016.
[cited by applicant]
Zhu et al., “The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs”, Aging Cell, vol. 14, No. 4, Aug. 2015, pp. 644-658, Epub Apr. 22, 2015.
[cited by applicant]
Co-Pending U.S. Application: Laberge et al., “Unit Dose of an Aryl Sulfonamide that is Effective for Treating Eye Disease and Averting Potential Vision Loss”, U.S. Appl. No. 16/007,880, filed Jun. 13, 2018.
[cited by applicant]
Co-Pending U.S. Application: Laberge et al., “Treatment for Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease”, U.S. Appl. No. 15/808,417, filed Nov. 9, 2017.
[cited by applicant]
Uthman et al., “Intra-Articular Therapy in Osteoarthritis” Postgrad. Med. J. (2003) vol. 79. pp. 449-453.
[cited by applicant]
Hashimoto T. et al., “Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation” Cardiovascular Research, 91(4). pp. 711-719, (2011).
[cited by applicant]
Collado M. et al., “Inhibition of the Phosphoinositide 3-kinase Pathway Induces a Senescence-Like Arrest Mediated by p27Kip1” The Journal of Biological Chemistry, 275(29), pp. 21960-21968. (2000).
[cited by applicant]
Hartung D. et al., “Resolution of Apoptosis in Atherosclerotic Plaque by Dietary Modification and Statin Therapy” Journal of Nuclear Medicine, 46(12) 2051-6, (2005).
[cited by applicant]
Suga S. et al., “An Inhibitory Effect on Cell Proliferation by Blockage of the MAPK/Estrogen Receptor/MDM2 Signal Pathway in Gynecologio Cancer.” Gynecol Oncol. May 2007; 105(2): 341-50.
[cited by applicant]
England B. et al., “. Current Understanding of the Role and Targeting of Tumor Suppressor p53 in Glioblastoma Multiforme” Tumour Biol. Aug. 2013;34(4):2063-74.
[cited by applicant]
Nag S. et al., “The MDM2-p53 Pathway Revisited” J Biomed Res. Jul. 2013 (4):254071.
[cited by applicant]
Setten RL. et al., “The Current State and Fturue of Directions of RNAi Therapeutics” Nat Rev Drug Discov. Jun. 18, 2019(6):421-446.
[cited by applicant]
Angart et al., “Design of siRNA Therapeutics from the Molecular Scale” Pharmaceuticals, 6(4), Jan. 24, 2013, pp. 440-468.
[cited by applicant]
Blagosklonny, “Aging and Immortality: Quasi-Programmed Senescence and It's Pharmacologic Inhibition,” Cell Cycle 5(18), Sep. 15, 2006, pp. 2087-2102.
[cited by applicant]
Fellman et al., “Functional Identification of Optimized RNAi Triggers Using a Massively Parallel Sensor Assay” Molecular Cell 41, Mar. 18, 2011, pp. 733-746.
[cited by applicant]
Kwok et al., “Determination of In Vivo RNA Structure in Low-Abundance Transcripts” Nature Communications, 4:2971, Dec. 16, 2013, 12 pages.
[cited by applicant]