|HAI LUI AUN ACUTUS010052335B2 OUT AT TUMUTUO ON (12 ) United States Patent ( 10 ) Patent No. : US 10 ,052 , 335 B2 Sitruk - Ware et al. ( 45 ) Date of Patent : * Aug . 21 , 2018 ( 54 ) NEUROPROTECTION AND MYELIN REPAIR ( 56 ) References Cited USING NESTORONE? U . S . PATENT DOCUMENTS ( 75) Inventors : Regine Sitruk -Ware , New York , NY 4 , 760 ,092 A * 7 / 1988 Weinreb . .. A61K 31 / 16 (US ) ; Michael Maria Helmut 514 /617 Schumacher , Kremlin - Bicêtre ( FR ) ; 6 ,891 , 081 B1 5 /2005 Stern et al. 8 , 026 , 228 B2 9 / 2011 Coelingh Bennink et al. Roberta Brinton , Rancho Palos Verdes, 2002/ 0049495 A1 4 / 2002 Kutryk et al. CA (US ) ; Martine El- Etr , Paris ( FR ) ; 2004 / 0087563 A1 5 / 2004 Mayerhofer Abdelmouman Ghoumari, Antony 2005 /0014731 A1 * 1 / 2005 Alt et al. .. 514 / 170 ( FR ) ; Rachida Guennoun , Villejuif 2006 /0205704 AL 9 / 2006 Scott et al. 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Brinton et al. , “ Progesterone Receptors: Form and Function in (65 ) Prior Publication Data Brain ” , Front Neuroendocrinol. May 2008 ; 29 ( 2 ): 313 -339 . Communication from PCT/ US2010 /053201 , dated Jan . 19 , 2011. US 2012 /0231052 A1 Sep . 13 , 2012 Confavreux et al. , “ Natural history of multiple sclerosis ” a unifying concept, Brain ( 2006 ) , 129 , 606 -616 . Confavreux et al. , “ Rate of pregnancy - related relapse in multiple Related U . S . Application Data sclerosis ” , The New England Journal of Medicine , vol. 339 , No . 5 , (60 ) Provisional application No. 61/ 279 ,320 , filed on Oct. Jul. 30 , 1998 . 19 , 2009 . (Continued ) Primary Examiner — Shirley V Gembeh (51 ) Int. Cl. (74 ) Attorney, Agent, or Firm — Lerner, David , A61K 31 /567 ( 2006 . 01 ) Littenberg , Krumholz & Mentlik , LLP A61K 31 /565 ( 2006 . 01 ) A61K 31 /00 ( 2006 . 01) (57 ) ABSTRACT A61K 31/ 57 ( 2006 . 01 ) Methods for treating neurodegeneration and / or myelination A61K 31 /573 ( 2006 .01 ) in patients are disclosed comprising treating the patient with A61K 31/ 575 ( 2006 .01 ) a progestin compound which exerts binding to progesterone A61K 31 /585 ( 2006 . 01) receptors and elicits progesterone- receptor- induced biologi A61K 45 / 06 ( 2006 .01 ) cal responses without interacting with the androgen receptor (52 ) U . S . CI. and without inducing androgen or glucocorticoid biological CPC . .. .. .. .. A61K 31/ 565 ( 2013 . 01 ) ; A61K 31/ 00 responses at a dosage sufficient to prevent or reduce neuro (2013 .01 ) ; A61K 31 /57 ( 2013 .01 ) ; A6IK degeneration . The progestin compound preferably com 31 /573 ( 2013 .01 ) ; A61K 31/ 575 ( 2013 .01 ) ; prises 16 -methylene - 17a - acetoxy - 19 -norpregn - 4 - ene - 3 ,20 A61K 31/ 585 ( 2013 .01 ) ; A61K 45 / 06 dione , and the methods include combining the progestin (2013 .01 ) compound with an estrogen compound to provide both ( 58 ) Field of Classification Search contraception and treatment for myelin repair and neurode CPC . .. .. .. .. .. .. A61K 31/ 57 ; A61K 31 / 565 generation . USPC . .. .. .. .. .. .. 514 / 170 See application file for complete search history . 15 Claims, 15 Drawing Sheets US 10 ,052 ,335 B2 Page 2 References Cited Nilsen et al ., “ Impact of progestins on estrogen - induced ( 56 ) neuroprotection : Synergy by progesterone and 19 - norprogesterone and antagonism by medroxyprogesterone acetate ” , Endocrinology OTHER PUBLICATIONS 143 ( 1 ) : p . 205 - 212 , Jan . 2002 . 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Patent Aug . 21, 2018 Sheet 1 of 15 US 10 ,052 ,335 B2 NES(50uM) NES(20uM) (50M) FIG.1 PROG NESTORONEPROMOTESMYELINATIONINORGANOTYPICCEREBELLARSLICECULTURES 161 * AWA AW PROG1204M) .6. 1 CONTROL o IMMUNOREACTIVITY MBP atent Aug . 21 , 2018 Sheet 2 of 15 US 10 ,052 , 335 B2 LYSO+NES +RU486 LYSO+RU486 LYSO+NES FIG.2 LYSO NES CTRL § õ % , INTENSITY STAINING MBP atent Aug . 21 , 2018 Sheet 3 of 15 US 10 ,052 ,335 B2 NESTORONE NORETHYNODREL NORGESTIMATE PROGESTERONE - * + - - * . * * * FIG.3 * EFFECTOFPROGESTINSTHATWEREMOREPROLIFERATIVETHANPROGESTERONE * * CONCENTRATION(M) * * 1.00E-12111098765 * * *. * * * * * * ** ? ? ? ? ? ? ? -80 CONTROL VEHICLE . VS INCORPORATION Brdu IN INCREASE PERCENT U . S . Patent Aug . 21, 2018 Sheet 4 of 15 US 10 , 052 , 335 B2 MEDROXYPROGESTERONEACETATE NORETHINDRONEACETATE PROGESTERONE - * 1.00E-5 1.00E-6 serveren FIG.4 PROGESTINSWITHNOORANTAGONISTICEFFECTONNEURAL PROGENITORCELLPROLIFERATION CONCENTRATION(M) * Anda* 1.00E-121110987 let na = = = = = = = -80L CONTROL VEHICLE . VS INCORPORATION