IP Library › Granted Patent US 12,383,521
Granted Patent B2
US 12,383,521 · App. 17/859,743 · Granted Aug 12, 2025

Treatment of diseases by concurrently eliciting remyelination effects and immunomodulatory effects using selective RXR agonists

Inventors: Roshantha A. Chandraratna (San Juan Capistrano, CA); Ethan Dmitrovsky (Hanover, NH); Elizabeth Nowak (West Lebanon, NH); Randolph Noelle (Plainfield, NH); Martin E. Sanders (Spring, TX)
Assignees: Io Therapeutics, Inc; Trustees of Dartmouth College
A61K31/192A61K31/216A61K31/343A61K31/353A61K31/47A61K31/4704A61K40/11
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Quick Facts
Patent No.
US 12,383,521
App. No.
17/859,743
Granted
Aug 12, 2025
Kind
B2
Abstract

The present specification provides RXR agonists with both remyelination promotion and immunomodulatory activities, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat a demyelination-related disorder by both promoting remyelination of neurons and modulating the immune system.

Claims (25)

1. A method of generating T regulatory cells (Treg) in vitro comprising culturing lymphocytes in the presence of an RXR agonist, wherein the RXR agonist is a compound having the structure of formula XXIX:

and

wherein the concentration of formula XXIX is at least 0.1 nM.

2. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of formula XXIX.

3. The method of claim 1 , wherein the lymphocytes are CD4+ lymphocytes.

4. The method of claim 1 , wherein the lymphocytes are peripheral blood lymphocytes.

5. The method of claim 1 , wherein the lymphocytes are obtained from leukapheresis.

6. The method of claim 1 , wherein the method further comprises culturing the lymphocytes cells in the presence of interleukin-2 (IL-2).

7. The method of claim 1 , wherein the method increases the number of differentiated Treg cells in the culture.

8. The method of claim 7 , wherein the differentiated Treg express FoxP3.

9. The method of claim 1 , wherein the method produces Treg cells with increased immunosuppressive activity.

10. A method of treating a demyelination-associated disorder comprising administering to a subject in need thereof Treg cells produced by the method of claim 1 .

11. The method of claim 10 , wherein the demyelination-associated disorder is multiple sclerosis.

12. The method of claim 10 , wherein the demyelination-associated disorder is amyotrophic lateral sclerosis.

13. The method of claim 10 , wherein the Treg are produced from lymphocytes isolated from the subject to be treated.

14. The method of claim 10 , wherein as a result of the administration of Treg, a Treg/T17 imbalance is corrected in the subject.

15. A method of growing oligodendrocytes or oligodendrocyte precursor cells in vitro comprising culturing oligodendrocytes or oligodendrocyte precursor cells in the presence of an RXR agonist, wherein the RXR agonist is a compound having the structure of formula XXIX:

and

wherein the concentration of formula XXIX is at least 0.1 nM.

16. The method of claim 15 , wherein the compound is a pharmaceutically acceptable salt of formula XXIX.

17. The method of claim 15 , wherein the cells are oligodendrocyte precursor cells.

18. The method of claim 15 , wherein the cells are oligodendrocytes.

19. A method for treating a demyelination-associated disorder, comprising administering to a subject in need thereof oligodendrocytes or oligodendrocyte precursor cells grown by the method of claim 15 .

20. The method of claim 19 , wherein the oligodendrocytes or oligodendrocyte precursor cells are isolated from the subject to be treated.

21. The method of claim 19 , wherein administering oligodendrocytes or oligodendrocyte precursor cells to a subject in need thereof results in remyelination of demyelinated neurons.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 22, 2023
From: CHANDRARATNA, ROSHANTHA A.; SANDERS, MARTIN E.
To: IO THERAPEUTICS, INC.
Reel/Frame 062770/0489 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 22, 2023
From: DMITROVSKY, ETHAN; NOWAK, ELIZABETH; NOELLE, RANDOLPH
To: TRUSTEES OF DARTMOUTH COLLEGE
Reel/Frame 062770/0728 →
Continuity (6)
Continuation 16736705 · Jan 7, 2020
Continuation 14507730 · Oct 6, 2014
Continuation In Part 13714051 · Dec 13, 2012
Provisional Application 61887529 · Oct 7, 2013
Provisional Application 61570182 · Dec 13, 2011
Related Publication 20220370386A1 · Nov 24, 2022
References Cited (366)
US 4756911A · Drost · 1988 [cited by applicant]
US 5378475A · Smith · 1995 [cited by applicant]
US 5455265A · Chandraratna · 1995 [cited by applicant]
US 5466861A · Dawson et al. · 1995 [cited by applicant]
US 5663367A · Vuligonda et al. · 1997 [cited by applicant]
US 5675033A · Vuligonda et al. · 1997 [cited by applicant]
US 5728846A · Vuligonda et al. · 1998 [cited by applicant]
US 5739338A · Beard et al. · 1998 [cited by applicant]
US 5763635A · Vuligonda et al. · 1998 [cited by applicant]
US 5773594A · Johnson et al. · 1998 [cited by applicant]
US 5776699A · Klein et al. · 1998 [cited by applicant]
US 5780647A · Vuligonda et al. · 1998 [cited by applicant]
US 5817836A · Vuligonda et al. · 1998 [cited by applicant]
US 5856490A · Teng · 1999 [cited by applicant]
US 5877207A · Klein et al. · 1999 [cited by applicant]
US 5917082A · Vuligonda et al. · 1999 [cited by applicant]
US 5919970A · Song et al. · 1999 [cited by applicant]
US 5952345A · Klein et al. · 1999 [cited by applicant]
US 5958954A · Klein et al. · 1999 [cited by applicant]
US 5965606A · Teng · 1999 [cited by applicant]
US 5998655A · Vuligonda et al. · 1999 [cited by applicant]
US 6008204A · Klein et al. · 1999 [cited by applicant]
US 6048873A · Vasudevan et al. · 2000 [cited by applicant]
US 6034242A · Vuligonda et al. · 2000 [cited by applicant]
US 6037488A · Song et al. · 2000 [cited by applicant]
US 6043381A · Vuligonda et al. · 2000 [cited by applicant]
US 6063768A · First · 2000 [cited by applicant]
US 6087505A · Vuligonda et al. · 2000 [cited by applicant]
US 6090810A · Klein et al. · 2000 [cited by applicant]
US 6114533A · Vuligonda et al. · 2000 [cited by applicant]
US 6117987A · Johnson et al. · 2000 [cited by applicant]
US 6147224A · Vuligonda et al. · 2000 [cited by applicant]
US 6187750B1 · Chein · 2001 [cited by applicant]
US 6211385B1 · Vuligonda et al. · 2001 [cited by applicant]
US 6218128B1 · Klein et al. · 2001 [cited by applicant]
US 6225494B1 · Song et al. · 2001 [cited by applicant]
US 6228848B1 · Klein et al. · 2001 [cited by applicant]
US 6235923B1 · Song et al. · 2001 [cited by applicant]
US 6313163B1 · Vuligonda et al. · 2001 [cited by applicant]
US 6313168B1 · Pacifici et al. · 2001 [cited by applicant]
US 6387950B2 · Nehme · 2002 [cited by applicant]
US 6403638B1 · Vuligonda et al. · 2002 [cited by applicant]
US 6521624B1 · Klein et al. · 2003 [cited by applicant]
US 6521641B1 · Klein et al. · 2003 [cited by applicant]
US 6538149B1 · Vuligonda et al. · 2003 [cited by applicant]
US 6555690B2 · Johnson et al. · 2003 [cited by applicant]
US 6610744B2 · Teng et al. · 2003 [cited by applicant]
US 6630463B2 · Kikuchi et al. · 2003 [cited by applicant]
US 6653483B1 · Johnson et al. · 2003 [cited by applicant]
US 6720423B2 · Vasudevan et al. · 2004 [cited by applicant]
US 6720425B2 · Johnson et al. · 2004 [cited by applicant]
US 6776984B1 · Schwartz · 2004 [cited by applicant]
US 6818775B2 · Johnson et al. · 2004 [cited by applicant]
US 6942980B1 · Klein et al. · 2005 [cited by applicant]
US 7048946B1 · Wong · 2006 [cited by applicant]
US 7105566B2 · Chandraratna et al. · 2006 [cited by applicant]
US 7166726B2 · Vuligonda et al. · 2007 [cited by applicant]
US 8101662B2 · Chandraratna · 2012 [cited by applicant]
US 9308186B2 · Chandraratna · 2016 [cited by applicant]
US 9655872B2 · Chandraratna · 2017 [cited by applicant]
US 9717702B2 · Chandraratna · 2017 [cited by applicant]
US 10039731B2 · Chandraratna · 2018 [cited by applicant]
US 10188618B2 · Chandraratna · 2019 [cited by applicant]
US 10590059B2 · Chandraratna et al. · 2020 [cited by applicant]
US 10596133B2 · Chandraratna · 2020 [cited by applicant]
US 10835507B2 · Chandraratna et al. · 2020 [cited by applicant]
US 10966950B2 · Sanders et al. · 2021 [cited by applicant]
US 20010037025A1 · Murray · 2001 [cited by applicant]
US 20020156054A1 · Klein et al. · 2002 [cited by applicant]
US 20020173631A1 · Johnson et al. · 2002 [cited by applicant]
US 20020193403A1 · Yuan et al. · 2002 [cited by applicant]
US 20030013766A1 · Lamph et al. · 2003 [cited by applicant]
US 20030077664A1 · Zhao et al. · 2003 [cited by applicant]
US 20030130341A1 · Li et al. · 2003 [cited by applicant]
US 20030144330A1 · Spiegelman · 2003 [cited by applicant]
US 20030219832A1 · Klein et al. · 2003 [cited by applicant]
US 20040049072A1 · Ardecky · 2004 [cited by applicant]
US 20040147611A1 · Yuan et al. · 2004 [cited by applicant]
US 20040037025A1 · Murray et al. · 2004 [cited by applicant]
US 20050004213A1 · Sinha et al. · 2005 [cited by applicant]
US 20050171151A1 · Yuan et al. · 2005 [cited by applicant]
US 20050181017A1 · Hughes · 2005 [cited by applicant]
US 20050244464A1 · Hughes · 2005 [cited by applicant]
US 20060286127A1 · Van Schaack et al. · 2006 [cited by applicant]
US 20070054882A1 · Klein et al. · 2007 [cited by applicant]
US 20070077652A1 · Peled et al. · 2007 [cited by applicant]
US 20070078129A1 · Lagu et al. · 2007 [cited by applicant]
US 20070122476A1 · Hanshew · 2007 [cited by applicant]
US 20070185055A1 · Jiang · 2007 [cited by applicant]
US 20070265449A1 · Vuligonda et al. · 2007 [cited by applicant]
US 20090004291A1 · Song · 2009 [cited by applicant]
US 20090136470A1 · Hilde et al. · 2009 [cited by applicant]
US 20090203720A1 · Zhao et al. · 2009 [cited by applicant]
US 20090209601A1 · Nagpal et al. · 2009 [cited by applicant]
US 20090227674A1 · Richon et al. · 2009 [cited by applicant]
US 20100298434A1 · Rouillard · 2010 [cited by applicant]
US 20110008437A1 · Altman · 2011 [cited by applicant]
US 20120115912A1 · Landreth · 2012 [cited by applicant]
US 20120238623A1 · Chandraratna · 2012 [cited by applicant]
US 20120309833A1 · Wagner et al. · 2012 [cited by applicant]
US 20130190395A1 · Chandraratna et al. · 2013 [cited by applicant]
US 20140235676A1 · Landreth · 2014 [cited by applicant]
US 20140286973A1 · Powell, Jr. · 2014 [cited by applicant]
US 20150038585A1 · Chandraratna et al. · 2015 [cited by applicant]
US 20150196517A1 · Chandraratna et al. · 2015 [cited by applicant]
US 20150342917A1 · Chandraratna et al. · 2015 [cited by applicant]
US 20160263189A1 · Burstein · 2016 [cited by applicant]
US 20170056348A1 · Chandraratna et al. · 2017 [cited by applicant]
US 20170119713A1 · Chandraratna et al. · 2017 [cited by applicant]
US 20170119714A1 · Chandraratna et al. · 2017 [cited by applicant]
US 20180064670A1 · Chandraratna et al. · 2018 [cited by applicant]
US 20180116985A1 · Chandraratna et al. · 2018 [cited by applicant]
US 20180263939A1 · Chandraratna et al. · 2018 [cited by applicant]
US 20180318241A1 · Chandraratna et al. · 2018 [cited by applicant]
US 20180369181A1 · Chandraratna et al. · 2018 [cited by applicant]
US 20190083441A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190117603A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190125705A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190201358A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190231726A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190298678A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190365681A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20190381022A1 · Chandraratna et al. · 2019 [cited by applicant]
US 20200155488A1 · Chandraratna et al. · 2020 [cited by applicant]
US 20200155489A1 · Chandraratna et al. · 2020 [cited by applicant]
US 20200163915A1 · Chandraratna et al. · 2020 [cited by applicant]
US 20200170985A1 · Chandraratna et al. · 2020 [cited by applicant]
US 20200190008A1 · Chandraratna et al. · 2020 [cited by applicant]
US 20200390736A1 · Sanders et al. · 2020 [cited by applicant]
US 20210077445A1 · Chandraratna et al. · 2021 [cited by applicant]
US 20210128503A1 · Chandraratna et al. · 2021 [cited by applicant]
US 20210128504A1 · Chandraratna et al. · 2021 [cited by applicant]
US 20210161874A1 · Chandraratna et al. · 2021 [cited by applicant]
US 20210205243A1 · Chandraratna et al. · 2021 [cited by applicant]
EP 2322147A1 · 2011 [cited by applicant]
EP 2556827A1 · 2013 [cited by applicant]
JP 2010280585A · 2010 [cited by applicant]
WO 1994012880A2 · 1994 [cited by applicant]
WO 1994014777 · 1994 [cited by applicant]
WO 1996039374A1 · 1996 [cited by applicant]
WO 1997009297A2 · 1997 [cited by applicant]
WO 1999008992A1 · 1999 [cited by applicant]
WO 1999033821A1 · 1999 [cited by applicant]
WO 1999063980A1 · 1999 [cited by applicant]
WO 2000020370A1 · 2000 [cited by applicant]
WO 2001007028A2 · 2001 [cited by applicant]
WO 2002089781A2 · 2002 [cited by applicant]
WO 2002089842 · 2002 [cited by applicant]
WO 2003027090A2 · 2003 [cited by applicant]
WO 2003062369 · 2003 [cited by applicant]
WO 2003078567 · 2003 [cited by applicant]
WO 2003093257A1 · 2003 [cited by applicant]
WO 2003101928 · 2003 [cited by applicant]
WO 2004046096 · 2004 [cited by applicant]
WO 2005013949A2 · 2005 [cited by applicant]
WO 2005027895A2 · 2005 [cited by applicant]
WO 2007022408A2 · 2007 [cited by applicant]
WO 2007041076A2 · 2007 [cited by applicant]
WO 2007041398 · 2007 [cited by applicant]
WO 2008157394A2 · 2008 [cited by applicant]
WO 2010132671A1 · 2010 [cited by applicant]
WO 2011006157A2 · 2011 [cited by applicant]
WO 2013020966 · 2013 [cited by applicant]
WO 2013090616A1 · 2013 [cited by applicant]
WO 2015059632A1 · 2015 [cited by applicant]
WO 2015066197A2 · 2015 [cited by applicant]
WO 2016144976A1 · 2016 [cited by applicant]
WO 2017075610 · 2017 [cited by applicant]
WO 2017075612A1 · 2017 [cited by applicant]
WO 2017155577A1 · 2017 [cited by applicant]
WO 2017155578A1 · 2017 [cited by applicant]
WO 2019046591A1 · 2019 [cited by applicant]
WO 2019060600A1 · 2019 [cited by applicant]
Silvestroff et al., Cuprizone-induced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination. Experimental Neurology, 235, pp. 357-367 (2012). [cited by applicant]
Smit et al., Bexarotene-induced hypothrodism: bexarotene stimulates the peripheral metabolism of thyroid hormones. J. Clin. Endocrinol. Metab., 92(7):2496-2499 (2007). [cited by applicant]
Suh et al., Prevention and treatment of experimental breast cancer with the combination of a new selective estrogen receptor modulator, Arzoxifene, and a new rexinoid, LG 100268. Clin Cancer Res, 8:3270-3275 (2002). [cited by applicant]
Takahashi et al., Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions. Journal of Medicinal Chemistry, vol. 45, No. 16, pp. 3327-3330 (2002). [cited by applicant]
Teng et al., Identification of highly potent retinoic acid receptor alpha-selective antagonists. Journal of Medicinal Chemistry, vol. 40, pp. 2445-2451 (1997). [cited by applicant]
Tesseur et al., Comment on ApoE-directed Therapeutics Rapidly Clear beta-Amyloid and Reverse Deficits in AD Mouse Models. Science, 340:924-e (2013). [cited by applicant]
Tovar-Y-Romo et al., Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy. Frontiers in Cellular Neuroscience, 8:Article 61 (2014). [cited by applicant]
Trillo et al., Ascending monoaminergic systems alterations in Alzheimer's disease. Translating basic science into clinical care. Neuroscience and Biobehavioral Riviews, 37:1363-1379 (2013). [cited by applicant]
Assaf et al., Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion. British Journal of Dermatology, 155, pp. 261-266 (2006). [cited by applicant]
Diab et al., Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis. Journal of Neuroimmunology… [cited by applicant]
Extended European Search Report, dated Oct. 1, 2019, for European Application No. 16893789.4 filed Oct. 31, 2016. [cited by applicant]
Farmer et al., Retinoic acid receptor ligands based on the 6-cyclopropyl-2,4-hexadienoic acid. Bioorganic & Medicinal Chemistry Letters, 13:261-264 (2003). [cited by applicant]
Hsu et al., Generation and characterization of monoclonal antibodies directed against the surface antigens of cervical cancer cells. Hybrid Hybridomics, vol. 23, No. 2, pp. 121-125 (2004)—abstract. [cited by applicant]
Uslu et al., Doxazosin: a new cytotoxic agent for prostate cancer? BJU International, vol. 85, pp. 672-675 (2000). [cited by applicant]
Veeraraghavalu et al, Comment on ApoE-directed Therapeutics Rapidly Clear beta-Amyloid and Reverse Deficits in AD Mouse Models. Science 340:924-f, 2013. [cited by applicant]
Volakakis et al., Nurr1 and Retinoid X Receptor ligands stimulate Ret signaling in dopamine neurons and can alleviate alpha-synuclein disrupted gene expression. J. Neurosci., 35(42):14370-14385 (2015). [cited by applicant]
Walkley et al., Retinoic acid receptor anatagonism in vivo expands the numbers of precursor cells during granulopoiesis. Leukemia, vol. 16, No. 9, pp. 1763-1772 (2002). [cited by applicant]
Wallen-MacKenzie et al., Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells. Genes and Development, 17: 3036-3047 (2003). [cited by applicant]
Wang et al., Selective brain penetrable Nurr1 transactivator for treating Parkinson's disease. Oncotarget 7 (7):7469-7479 (2016). [cited by applicant]
Wang, (2013) Slide presentation at the Symposium on IRX4204 at The 11th International Conference on Alzheimer's and Parkinson's Diseases: The Novel RXR agonist IRX4204 as a Potential Disease-Modifying Agent in Alzheimer… [cited by applicant]
WebMD, Common Drugs and Medicines to Treat Multiple Sclerosis; Drugs & Medications Search, accessed May 12, 2017; pp. 1-3. [cited by applicant]
Xiao et al., Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of TH17 cells by enhancing TFG-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. The Journal of Immunolog… [cited by applicant]
Xiao et al., Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway. Journal of Biological Chemistry, vol. 278, No. 32, pp. 29954-29962 (2003). [cited by applicant]
Yacila & Sari, Potential Therapeutic Drugs and Methods for the Treatment of Amyotrophic Lateral Sclerosis. Curr. Med. Chem., 21(31):3583-3593 (2014). [cited by applicant]
Yamada et al., Retinoid X receptor ligands: a patent review (2007-2013). Expert Opin. Ther. Patents, 24(4):443-452 (2014). [cited by applicant]
Zapata-Gonzalez et al., 9-cis-retinoic acid (9cRA), a retinoid X receptor (RXR) ligand, exerts immunosuppressive effects on dendritic cells by RXR-dependent activation: inhibition of peroxisome proliferator-activated re… [cited by applicant]
Zhang et al., Thyroid hormone potentially benefits multiple sclerosis via facilitating remyelination. Mol. Neurobiol., 53, pp. 4406-4416 (2016). [cited by applicant]
Jones et al., Animal models of schizophrenia. British Journal of Pharmacology, 164:1162-1194 (2011). [cited by applicant]
Kabbinavar et al., An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC). Journal of Clinical Oncology, vol. 32, No. 15 Suppl, p. 50… [cited by applicant]
Kim, Chang H. Regulation of FoxP3+ regulatory T cells and Th17 cells by retinoids. Clinical and Developmental Immunology, vol. 2008, 12 pages (2008). [cited by applicant]
Koivusalo et al., The cytotoxicity of chemotherapy drugs varies in cervical cancer cells depending on the p53 status. Cancer Biology and Therapy, vol. 3278(11):1177-1183 (2004). [cited by applicant]
Liu et al., Mechanism of selective retinoid X receptor agonist-induced hypothroidism in the rat. Endocrinology, 143 (8):2880-2885 (2002). [cited by applicant]
Singaporean Written Opinion, dated Sep. 26, 2019, for Singaporean Application No. 11201807250P filed on Oct. 31, 2016. [cited by applicant]
Singaporean Written Opinion, dated Sep. 16, 2019, for Singaporean Application No. 11201807255Y filed on Oct. 31, 2016. [cited by applicant]
Supplementary European Search Report for European Patent Application Serial No. 16861057 mailed on May 22, 2019. [cited by applicant]
Supplementary European Search Report for European Patent Application Serial No. 16861059 mailed on May 16, 2019. [cited by applicant]
Vuligonda et al., Enantioselective syntheses of potent retinoid X receptor ligands: Differential biological activities of individual antipodes. J. Med. Chem., 44. pp. 2298-2303 (2001). [cited by applicant]
Inoue et al., Rexinoids isolated from Sophora tonkinensis with a gene expression profile distinct from the synthetic rexinoid bexarotene. J. Nat. Prod. 77:1670-1677 (2014). [cited by applicant]
“Intranasal medication delivery—brief overview of the concept.” Intranasal.net. Accessed Feb. 24, 2017. [cited by applicant]
Io Therapeutics, Inc. Brochure for the Symposium on IRX4204 at The 11th International Conference on Alzheimer's and Parkinson's Diseases (2013). [cited by applicant]
Jassem et al., A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naïve-patients with advanced or metastatic non-small cell lung cancer (NSCLC). Journal … [cited by applicant]
Johnson et al., Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorganic & Medicinal Chemistry, vol. 7, No. 7, pp. 1321-1338 (1999). [cited by applicant]
Kagechika et al., Synthetic retinoids: recent developments concerning structure and clinical utility. Journal of Medicinal Chemistry, vol. 48, No. 19: 5875-5883, (2005). [cited by applicant]
Kawata et al., RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects. J. Med. Chem. 58(2):912-926 (2015). [cited by applicant]
Kimura et al., IL-6: Regulator of Treg/Th17 balance. Eur. J. Immunol., 40:1830-1835 (2010). [cited by applicant]
Kim et al., Immunopathogenesis and therapy of cutaneous T cell lymphoma. Science in Medicine, The JCI Textbook of Molecular Medicine. Editors Marks et al., p. 164 (2007). [cited by applicant]
Klein et al., Cardiovascular involvement in general medial conditions. Thyroid disease and the heart. Circulation, 116:1725-1735 (2007). [cited by applicant]
Klein et al., Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists. The Journal of Biological Chemistry, vol. 271, No. 37, pp. 22692-22696, 1996. [cited by applicant]
Knol et al., Absence of modulation of CD4+CD25high regulatory T cells in CTCL patients treated with bexarotene. Experimental Dermatology, 19:e95-e102 (2010). [cited by applicant]
Kotani et al., A naturally occurring rexinoid, honokiol, can serve as a regulator of various retinoid X receptor heterodimers. Biol. Pharm. Bull. 35(1):1-9 (2012). [cited by applicant]
Laclair et al., Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice, Molecular Neurodegeneration 8:18 (10pp) (2013). [cited by applicant]
Lampen et al., Effects of receptor-selective retinoids on CYP26 gene expression and metabolism of all-trans-retinoic acid in intestinal cells. Drug Metabolism & Disposition, vol. 29, No. 3, pp. 742-747 (2001). [cited by applicant]
Lefebvre et al., Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol. Metab. 21:676-683 (2010). [cited by applicant]
Levasque et al., Nur77 and retinoid X receptors: crucial factors in dopamine-related neuroadaptation. Trends in Neuroscience, vol. 30, No. 1, pp. 22-30 (2007). [cited by applicant]
Li et al., Distinct Mechanisms of Glucose Lowering by Specific Agonists for Peroxisomal Proliferator Activated Receptor gamma and Retinoic Acid X Receptors, Journal of Biological Chemistry 280(46):38317-38327, 2005. [cited by applicant]
Liu et al., Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo. Clin Cancer Res, 11(13):4851-4856 (2005). [cited by applicant]
Lowenthal et al., The Ethics of Early Evidence—Preparing for a Possible Breakthrough in Alzheimer's Disease, N Engl J Med., 367(6):488-490 (2012). [cited by applicant]
MacChia et al., RXR receptor agonist suppression of thryoid function: central effects in the absence of thyroid hormone receptor. Am. J. Physiol. Endocrinol. Metab., vol. 283, pp. E326-E331 (2002). [cited by applicant]
Mangelsdorf et al., Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes and Development 6:329-344 (1992). [cited by applicant]
Marketwire 2012: IRX4204 as a Potential Disease-Modifying Treatment for Alzheimer's Disease. [cited by applicant]
Marks et al., Science in Medicine: The JCI textbook of Molecular Medicine, p. 164 (2007). [cited by applicant]
Martin et al., Induction of the fatty acid transport protein 1 and acyl-CoA synthase genes by dimer-selective rexinoids suggests that the peroxisome proliferator-activated receptor-retinoid X receptor heterodimer is the… [cited by applicant]
McFarland et al., Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease. ACS Chem. Neurosci. 4:1430-1438 (2013). [cited by applicant]
Migliore, Intranasal Delivery of GDNF for the Treatment of Parkinson's Disease. Doctoral Thesis, Pharmaceutical Sciences, Northeastern University, Boston, MA (2008). [cited by applicant]
Miller et al., Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol., 15(2):790-795 (1997). [cited by applicant]
Monahan et al., Neuroinflammation and peripheral immune infiltration in Parkinson's disease: an autoimmune hypothesis. Cell Transplant, 17:363-372 (2008). [cited by applicant]
Morris & Burns, Insulin: An Emerging Treatment for Alzheimer's Disease Dementia? Curr. Neurol. Neurosci. Rep. 12(5):520-527 (2012). [cited by applicant]
Munhoz et al., Parkinson's disease and thyroid dysfunction. Parkinsonism & Related Disorders, 10(6):381-383 (2004). [cited by applicant]
National Multiple Sclerosis Society, Medications, accessed May 12, 2017, pp. 1-5. [cited by applicant]
Natrajan et al., Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain A Journal of Neurology, 138:3581-3597 (2015). [cited by applicant]
Nishimaki-Mogami et al., The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines. Biochemical Pharmacology, 76: 1006-1013 (2008). [cited by applicant]
Ohsawa et al., Modification of the lipophilic domain of RXR agonists differentially influences activation of RXR heterodimers. ACS Med Chem Lett., 1:521-525 (2010). [cited by applicant]
Olson et al., Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease. Curr Opin Pharmacol. 26:87-95 (2016). [cited by applicant]
Park et al., Salvage chemotherapy of gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving survival of lymphoma (CISL) trial. An… [cited by applicant]
Perlmann et al., A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes & Develop. 9:769-782 (1995). [cited by applicant]
Petty et al., Weekly paclitaxel (Taxol®), carboplatin (Paraplatin®), and bexarotene (Tagretin®) for the treatment of patients with advanced non-small cell lung cancer: Efficacy results from a Phase I/II study. Journal o… [cited by applicant]
Pierrot et al., Targretin Improves Cognitive and Biological Markers in a Patient with Alzheimer's Disease. Journal of Alzheimer's Disease, 49:271-276 (2016). [cited by applicant]
Price et al., Comment on ApoE-directed Therapeutics Rapidly Clear beta-Amyloid and Reverse Deficits in AD Mouse Models. Science 340:924-d (2013). [cited by applicant]
Ramaswamy et al., Trophic factors therapy in Parkinson's disease. Prog. Brain Res., 175:201-216 (2009). [cited by applicant]
Ramlau et al., Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naïve patients with advanced or metastic non-small-cell lung cancer: SPIRIT I. J… [cited by applicant]
Reynolds et al., Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegneration in a model of Parkinson's disease. J. Immunol., vol. 184, pp. 2261-2271 (2010). [cited by applicant]
Riancho et al., Neuroprotective effect of bexarotene in SOD1G93A mouse model of amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience 9:Article 250 (2015). [cited by applicant]
Rigas et al., Emerging role of rexinoids in non-small cell lung cancer: Focus on bexarotene. The Oncologist, 10:22-33 (2005). [cited by applicant]
Rizvi et al., A phase I study of LGD1069 in adults with advanced cancer. Clin. Cancer Res., 5:1658-1664 (1999). [cited by applicant]
Sacchetti et al., Requirements for heterodimerization between orphan nuclear receptor Nurr1 and Retinoid X Receptors. The Journal of Biological Chemistry, 277(38):35088-35096 (2002). [cited by applicant]
Salama et al., Role of L-thyroxin in counteracting rotenone induced neurotoxocity in rats. Environmental Toxicology and Pharmacology, 35:270-277 (2013). [cited by applicant]
Sherman et al., Central hypothyroidism associated with retinoid X receptor-selective ligands. The New England Journal of Medicine, vol. 340, No. 14, pp. 1075-1079 (1999). [cited by applicant]
Alcala-Barraza et al., Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS. Journal of Drug Targeting, 18(3):179-190 (2009). [cited by applicant]
Altucci L et al., RAR and RXR modulation in cancer and metabolic disease. Nature Review Drug Discovery, vol. 6: 793-810 (2007). [cited by applicant]
Alzforum 2013: Can Cancer Therapy Be Neurodegenerative Wonder Drug? [cited by applicant]
Annerbo et al., Review Article: A clinical review of the association of thyroid stimulating hormone and cognitive impairment. ISRN Endocrinology, vol. 2013, Article ID 856017, 6 pages (2013). [cited by applicant]
Balasubramanian et al., Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid. Carcinogenesis, 2004, vol. 25, No. 8, pp. 1377-1385. [cited by applicant]
Balducci et al., The Continuing Failure of Bexarotene in Alzheimer's Disease Mice. J Alzheimers Dis., 46:471-482 (2015). [cited by applicant]
Benson et al., All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. The Journal of Experimental Medicine, vol. 204, No. 8, pp. 1765-1… [cited by applicant]
Beyer et al., Weight change and body composition in patients with Parkinson's disease. J. Am. DietAssoc., vol. 95, pp. 979-983 (1995). [cited by applicant]
Bilbao et al., Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol. Med., 6(11):1423-1435 (2014). [cited by applicant]
Blumenschein et al., A randomized phase III trial comparing bexarotene/carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC). … [cited by applicant]
Bordoni et al., Bexarotene improves TTP in untreated, advanced NSCLC, when given in combination with carboplalin/paclitaxel. Journal of Clinical Oncology, ASCO 2005 Annual Meeting, Abstract 7270. [cited by applicant]
Breen et al., Regulation of Thyroid-Stimulating Hormone beta-Subunit and Growth Hormone Messenger Ribonucleic Acid Levels in the Rat: Effect of Vitamin A Status, Endocrinology 136:543-9 (1995). [cited by applicant]
Cal et al., Doxazosin: a new cytotoxic agent for prostate cancer? BJU Int. 85:672-675 (2000). [cited by applicant]
Calza et al., Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis. PNAS, vol. 99, No. 5, pp. 3258… [cited by applicant]
Coya et al., Retinoic Acid Inhibits In Vivo Thyroid-Stimulating Hormone Secretion, Life Sciences, Pharmacology Letters, 60:247-50, 1997. [cited by applicant]
Cramer et al., ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science, 335(6075): 1503-1506 (2012). [cited by applicant]
Crowe et al.,A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to pe… [cited by applicant]
Cummings et al., Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimer's Research & Therapy, 8:4 (2016). [cited by applicant]
Debnath & Berk, Th17 Pathway-Mediated Immunopathogenesis of Schizophrenia: Mechanisms and Implications. Schizophrenia Bulletin, 40(6):1412-1421 (2014). [cited by applicant]
Dell'Acqua ML et al., Functional and molecular evidence of myelin- and neuroprotection by thyroid hormone administration in experimental allergic encephalomyelitis. Neuropath. Appl. Neurobiol., 38:454-470 (2012). [cited by applicant]
D'Intino G et al., Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by corrected tissue hypothyroidism. J Neuroendocrin., 23:778-790 (2… [cited by applicant]
Dore et al., Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity. Proc. Natl. Acad. Sci. USA, 94:4772-4777 (1997). [cited by applicant]
Duvic et al., Phase 2 and 3 Clinical Trial of Oral Bexarotene (Targretin Capsules) for the Treatment of Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma, Arch Dermatol. 137:581-593, 2001. [cited by applicant]
Estephan et al., Phase II trial of gemcitabine (G), carboplatin (C) and bexarotene (B) in patients (pts) with newly diagnosed, locally-advanced or metastatic non-small cell carcinoma of the lung. Journal of Clinical Onc… [cited by applicant]
Elias et al., Retinoic acid inhibits TH17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood, vol. 111, No. 3, pp. 1013-1020 (2008). [cited by applicant]
Fitz et al., Comment on ApoE-directed Therapeutics Rapidly Clear beta-Amyloid and Reverse Deficits in AD Mouse Models. Science 340:924-c (2013). [cited by applicant]
Franco et al., Thyroid hormones promote differentiation of oligodendrocyte progenitor cells and improve remyelination after cuprizone-induced demyelination. Experimental Neurology, 212, pp. 458-467, 2008 (2008). [cited by applicant]
Freiherr et al., Intranasal Insulin as a Treatment for Alzheimer's Disease: A Review of Basic Research and Clinical Evidence. CNS Drugs 27:505-514 (2013). [cited by applicant]
Friling et al., Activation of retinoid X receptor increases dopamine cell survival in models for Parkinson's disease. BMC Neuroscience, 10: 146 (2009). [cited by applicant]
Fu et al., Thyroid hormone prevents cognitive deficit in a mouse model of Alzheimer's disease. Neuropharmacology, 58:722-729 (2010). [cited by applicant]
Gibb et al., The substantia nigra and ventral tegmental area in Alzheimer's disease and Down's sydrome. J. Neurol. Neurosurg. and Psychiatry, 52:193-200 (1989). [cited by applicant]
Golub et al., Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring. Science, vol. 286, Oct. 15, 1999, pp. 531-537. [cited by applicant]
Gonzalez et al., T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J Neuroinflam 11:201-212 (2014). [cited by applicant]
Govindan et al., Phase II trial of bexarotene capsules in patients with non-small-cell lung cancer (NSCLC) who have failed at least 2 prior systemic therapies for Stage IIIB/IV disease. Journal of Clinical Oncology, 200… [cited by applicant]
Graber et al., Protective autoimmunity in the nervous system. Pharmacol. Therapeut., 121:147-159 (2009). [cited by applicant]
Haugen et al., The Thyrotrope-Restricted Isoform of the Retinoid-X Receptor-y1 Mediates 9-cis-Retinoic Acid Suppression of Thyrotropin-beta Promoter Activity. Molecular Endocrinology 11:481-9, 1997. [cited by applicant]
Henkel et al., Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol. Med., 5:64-79 (2012). [cited by applicant]
Hu et al., Imbalance between IL-17A-Producing Cells and Regulatory T Cells during Ischemic Stroke. Mediators of Inflammation 2014: Article ID 813045, 2014. [cited by applicant]
Huang et al., Retinoid X receptor gamma signaling accelerates CNS remyelination, Nature Neuroscience, 14(1): 45-53, 2011 (Epub Dec. 5, 2010). [cited by applicant]
International Search Report and Written Opinion mailed Mar. 28, 2013 for International Application Serial No. PCT/US2012/069566 filed on Dec. 13, 2012. [cited by applicant]
International Search Report and Written Opinion mailed Jan. 5, 2017 for International Application Serial No. PCT/US2016/059770 filed Oct. 31, 2016. [cited by applicant]
International Search Report for PCT/US2007/011730 mailed May 2, 2008. [cited by applicant]
International Search Report and Written Opinion mailed on Sep. 25, 2007 for International Application No. PCT/US2006/038252 filed on Oct. 2, 2006. [cited by applicant]
International Search Report and Written Opinion mailed on Dec. 29, 2016 for International Application No. PCT/US2016/059775 filed on Oct. 31, 2016. [cited by applicant]
International Search Report and Written Opinion mailed on Jan. 10, 2017 for International Application No. PCT/US2016/059776 filed on Oct. 31, 2016. [cited by applicant]
International Search Report and Written Opinion mailed on Dec. 29, 2016 for International Application No. PCT/US2016/059779 filed on Oct. 31, 2016. [cited by applicant]
International Search Report and Written Opinion mailed on May 22, 2017 for International Application No. PCT/ JS2016/059772 filed on Oct. 31, 2016. [cited by applicant]
International Search Report and Written Opinion mailed on Jan. 18, 2019 for International Application No. PCT/US2018/052031 filed on Sep. 20, 2018. [cited by applicant]
International Search Report and Written Opinion mailed on Dec. 11, 2018 for International Application No. PCT/US2018/048876 filed on Aug. 30, 2018. [cited by applicant]
Alsudais et al., Retinoid X receptor-selective signaling in the regulation of Akt/protein kinase B isoform-specific expression. The Journal of Biological Chemistry, vol. 291, No. 6, pp. 3090-3099 (2015). [cited by applicant]
Aranami et al., Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergology International, 57:115-120 (2008). [cited by applicant]
Certo et al., Activation of RXXR/PPARy underlies neuroprotection by bexarotene in ischemic stroke. Pharm. Resc. 102:298-307 (2015). [cited by applicant]
Chinese Office Action, dated May 21, 2020, for Chinese Patent Application No. 201680083364.8 (original and translation included). [cited by applicant]
Extended European Search Report for EP 16861057, mailed Jul. 6, 2019. [cited by applicant]
Graeppi-Dulac et al., Endocrine Side-Effects of Anti-Cancer Drugs: The impact of retinoids on the thryoid axis. European Journal of Endocrinology, 170(6), R253-R262 (2014). [cited by applicant]
Lalloyer et al., Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism in the liver. Arterioscler Thromb Vasc Biol 29(10):1488-1495 (2009). [cited by applicant]
Liby et al., A new rexinoid, NXR194204, prevents carcinogenesis in both the lung and mammary gland. Clin Cancer Res, 13(20):6237-6243 (2007). [cited by applicant]
Mor et al., Autoimmune encephalomyelitis and uveitis induced by T cell immunity to self beta-synuclein. The Journal of Immunology, 170:628-634 (2003). [cited by applicant]
Reagan-Shaw et al., Dose translation from animal to human studies revisted. FASEB J, 22:659-661 (2007). [cited by applicant]
Wikipedia, Schizophrenia, https://www.nimh.nih.gov/health/statistics/schizophrenia.html, accessed Feb. 20, 2020. [cited by applicant]
Bendele, Animal models of rheumatoid arthritis. J Musculoskel Neuron Interact, 1(4):377-385 (2001). [cited by applicant]
Harris, Retinoid therapy for rheumatoid arthritis. Annals of Internal Medicine, vol. 100(1), pp. 146-147 (1984). [cited by applicant]
Mucida et al., Supplemental Online Material: Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid. Retrieved on Mar. 5, 2021. Retrieved from internet, url:www.sciencemag.org/cgi/conent/full/1… [cited by applicant]
Mucida et al., Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid. Science, vol. 317 (5835), pp. 256-260 (2007). [cited by applicant]
Waite et al., Review Article: Th17 response and inflammatory autoimmune diseaes. International Journal of Inflammation, vol. 2012, Article ID 819467, 10 pp (2011). [cited by applicant]
Wikipedia, Experimental autoimmune encephalomyelitis. https://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitis, accessed Jul. 1, 2019 (last edited on Feb. 10, 2019). [cited by applicant]
Zhao et al., Application of thyroid hormone in animal models of multiple sclerosis. Drug Evaluation Research, 39 (1):148-151 (2016). [cited by applicant]
Andreaone et al., Cerebral atrophy and white matter disruption in chronic schizophrenia. EUR Arch Psychiatry Clin Neurol 257:3-11 (Feb. 2007). [cited by applicant]
Andreaone et al., Cortical white-matter microstructure in schizophrenia. British J Psychiatry 191:113-119 (Aug. 2007). [cited by applicant]
Banati et al., Inflammatory reaction in experimental autoimmune encephalomyelitis (EAE) is accompanied by a microglial expression of the betaA4-amyloid precursor protein (APP). Gila 14:209-215 (1995). [cited by applicant]
Becher et al., Th17 cytokines in autoimmune neuro-inflammation. Curr Opin Immunol 23(6):707-712 (2011). [cited by applicant]
Bettelli et al., Induction and effector functions of Th17 cells. Nature 453(7198):1051-1057 (2008). [cited by applicant]
Chandraratna et al., Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimune encephalomyelitis. Am J Transl Res 8(2):1016-1026 (2016). [cited by applicant]
Davis et al., White matter changes in schizoprenia—Evidence for myelin-related dysfunction. Arch Gen Psychiatry 60:443-456 (2003). [cited by applicant]
Debnath & Berk, Functional implications of the IL-23/IL-17 immune axis in schizophrenia. Mol Neurobiol, 54:8170-8178 (2017). [cited by applicant]
Ding et al., Activation of Th17 cells in drug naïve, first episode schizophrenia. Progress in Neuro-Pyschopharmacology & Biological Psychiatry, 51:78-82 (2014). [cited by applicant]
Domingues et al., Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLOS One, 5(11):e15531 (2010). [cited by applicant]
Drexhage et al., An activated set point of T-cell monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro- and anti-inflammatory forces. International Journal of Neuropsychopharmacology, … [cited by applicant]
Flygt et al., Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat. European Journal of Neuroscience 38:2153-2165 (2013). [cited by applicant]
Flynn et al., Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Molecular Psychiatry, 8:811-820 (2003). [cited by applicant]
Gilgun-Sherki et al., Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Research, 989:196-201 (2003). [cited by applicant]
Haqqani et al., Intercellular interactomics of human brain endothelial cells and Th17 lymphocytes: a novel strategy for identifying therapeutic targets of CNS inflammation. Cardiovascular Psychiatry and Neurology 2011: … [cited by applicant]
Inglese et al., Therapeutic strategies in multiple sclerosis: A focus on neuroprotection and repair and relevance to schizophrenia. Schizophrenia Research, 161:94-101 (2015). [cited by applicant]
Johnson et al., Axonal pathology in traumatic brain injury. Exp Nuerol, 246:35-43 (2013). [cited by applicant]
Kebir et al., Human Th17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 13(10):1173-1175 (2007). [cited by applicant]
Komiyama et al., IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol., 177:566-573 (2006). [cited by applicant]
Koster et al., Emerging drugs for schizophrenia: an update. Expert Opin Emerging Drugs, 19(4):511-531 (2014). [cited by applicant]
Li et al., Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia. Psychiatry Research, 246:700-706 (2016). [cited by applicant]
Mai et al., T helpher 17 cells interplay with CD4+CD25highFoxp3+ Tregs in regulation of inflammations and autoimmune diseases. Front Biosci, 15:986-1006 (2010). [cited by applicant]
Miller et al., Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry, 70(7):663-671 (2011). [cited by applicant]
Miller et al., Meta-analysis of lymphocytes in schizophrenia: Clinical status and antipsychotic effects. Biol Psychiatry, 73(10):993-999 (2013). [cited by applicant]
Moriya et al., Edaravone, a free radical scavenger, ameliorates experimental autoimmune encephalomyelitis. Neuroscience Letters, 440:323-326, 2008. [cited by applicant]
Murphy et al., Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behavior and Immunity, 24:641-651 (2010). [cited by applicant]
Pastemak et al., The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia. Schizophrenia Research, 161(1):113-118 (2015). [cited by applicant]
Rostami et al., Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J. Neurol Sci, 330:76-87 (2013). [cited by applicant]
Saresella et al., T helper-17 activation dominates the immunologic milieu of both amyotrophic lateral sclerosis and progressive multiple sclerosis. Clincal Immunology, 148:79-88 (2013). [cited by applicant]
Schneider et al., Hyperphosphorylation and aggregation of Tau in experimental autoimmune encephalomyelitis. J Biol Chem 279(53):55833-55839 (2004). [cited by applicant]
Segal, Th17 cells in autoimmune demyelinating disease. Semin Immunopathol, 32(1):71-77 (2010). [cited by applicant]
Smith, A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Medical Hypotheses, 39:248-257 (1992). [cited by applicant]
Stromnes et al., Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med, 14 (3):337-342 (2008). [cited by applicant]
Sugiyama et al., Dysfunctional blood and target tissue CD4+ CD25high regulatory T cells in psoriasis: Mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol, 174:164-173 (2005). [cited by applicant]
Rittenhouse et al., Thyroxine administration prevents streptococcal cell wall-induced inflammatory responses. Endocrinology, 138(4):1434-1439 (1997). [cited by applicant]
Singaporean Written Opinion, dated Apr. 22, 2021, for Singaporean Application No. 11201807255Y filed on Oct. 31, 2016. [cited by applicant]
Hueber et al., Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Science Translational Medicine, vol. 2, Issue 52, 52ra72 (2010). [cited by applicant]
Science Daily [online] (2007), Potential role for retinoic acid in autoimmune and inflammatory diseases identified, La Jolla Institute for Allergy and Immunology p. 1-3 Retrieved from the internet, Retrieved on Mar. 5, … [cited by applicant]
Trapp et al., Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278-785 (1998). [cited by applicant]