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| Hai Lui a Un Acut out at Tumutuo On |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. ( FR ) FOREIGN PATENT DOCUMENTS ( 73 ) Assignee : The Population Council, Inc. , New CN 102657661 A 9 /2012 York , NY (US ) CN 102688247 A 9 / 2012 WO 2003097071 A1 11 /2003 ( * ) Notice : Subject to any disclaimer, the term of this WO WO2008 / 150547 Al * 12 / 2008 patent is extended or adjusted under 35 Wo 2011049948 A2 4 / 2011 U . S . C . 154 (b ) by 489 days. This patent is subject to a terminal dis OTHER PUBLICATIONS claimer . Health , Jun . 2017 . * Journal of the Neurological Sciences 265 ( 2008 ) 89 -92 . * Australian Examination Report for Application No. 2010308308 (21 ) Appl . No. : 13/ 500 , 008 dated Aug . 23 , 2013 . Lenzi E et al : “ Central modifications of allopregnanolone and (22 ) PCT Filed : Oct . 19 , 2010 beta - endorphin following subcutaneous administration of Nestorone ” , Journal of Steroid Biochemistry and Molecular Biol ogy , Elsevier Science Ltd ., Oxford , GB , vol . 116 , No . 1 - 2 , Aug. 1 , ( 86 ) PCT No .: PCT/ US2010 / 053201 2009 (Aug . 1 , 2009 ) , pp . 15 - 20 , XP026211788 . $ 371 ( c ) ( 1 ) , Schumacher et al: “ Progesterone and progestins : neuroprotection and myelin repair ” , Current Opinion in Pharmacology , Elsevier ( 2 ) , ( 4 ) Date : May 31, 2012 Science Publishers , NL , vol . 8 , No. 6 , Dec . 1 , 2008 (Dec . 1 , 2008 ) , pp . 740 - 746 , XP025669940 . ( 87) PCT Pub . No. : W02011 /049948 Birgbauer et al . , “ Lysolecithin induces demyelination in Vitro in a cerebellar slice culture system ” , Journal of Neuroscience Research PCT Pub . Date : Apr. 28 , 2011 78 : 157 - 166 (2004 ) . 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 . Patani et al ., “ Remyelination can be extensive in multiple sclerosis Confavreux et al. , :Course and Prognosis of Multiple Sclerosis despite a long disease course ” , Neuropathalogy and Applied Assessed by the Computerized Data Processing of 349 Patients , Neurobiology (2007 ) , 33 , 277 -287 . Brain ( 1980 ) , 103 , pp . 281 - 300 . Patrikios et al. , “ Remyelination is extensive in a subset of multiple Dutta et al. , “ Pathogenesis of axonal and neuronal damage in sclerosis patients ” , Brain ( 2006 ) , 129 , 3165 -3172 . multiple sclerosis ” , Neurology 2007 ; 68 ; S22 -S31 . Pugliatti et al. , “ The epidemiology of multiple sclerosis in Europe ” , Ghoumari et al ., “ Progesterone and its metabolites increase myelin Europena Journal of Neurology 2006 , 13 : 700 -722 . basic protein expression in organotypic slice cultures of rat cerebel Sayeed et al. , “ Progesterone inhibits ischemic brain injury in a rat lum ” , Journal of Neurochemistry , 2003 , 86 , 848 - 859 . model of permanent middle cerebral artery occlusion ” , Restorative Ghoumari et al. , “ Progesterone increases oligodendroglial cell pro Neurology and Neuroscience 25 ( 2007 ) 151- 159 . liferation in rat cerebellar slice cultures ” , Neuroscience 135 (2005 ) Sitruk -Ware , Regine , “ New progestagens for contraceptive use” , 47 - 58 . Human Reproduction Update , vol. 12 , No. 2 , pp . 169 - 178 , 2006 . Gibson et al ., " Progesterone for the treatment of experimental brain Extended European Seach Report for Application No . EP13199399 injury ; a systematic review ” , Brain (2008 ), 131, 318 -328 . dated Mar . 19 , 2014 . Holmqvist et al ., “ Symptoms of multiple sclerosis in women in Hussain Rashad et al: “ Progesterone and Nestorone Facilitate Axon relation to sex steroid exposure ” , Maturitas 54 ( 2006 ) 149 - 153 . Remyelination : A Role for Progesterone Receptors ” , Endocrinol International Search Report and Written Opinion , PCT/ US2010 / ogy , vol. 152 , No . 10 , Oct. 2011 ( Oct . 2011 ) , pp . 3820 - 3831, 053201 , dated Apr. 19 , 2011 . XP055106124 . Irvine et al ., “ Remyelination protects axons from demyelination Liu Ailing et al : " Progesterone Receptors: A Key for Neuroprotec associated axon degeneration ” , Brain ( 2008 ) , 131 , 1464 - 1477 . tion in Experimental Stroke ” , Endocrinology , vol. 153 , No . 8 , Aug. Kornek et al. , “ Multiple sclerosis and chronic autoimmune encepha 2012 ( Aug . 2012 ) , pp . 3747 -3757 , XP055106120 . lomyelitis / A comparative quantitative study of axonal injury in Stein et al : “ Progesterone exerts neuroprotective effects after brain active , inactive , and remyelinated lesions” , American Journal of injury ” , Brain Research Reviews, Elsevier, NL , vol. 57 , No . 2 , Mar . Pathology , vol . 157 , No . 1 , Jul. 2000 . 14 , 2008 (Mar . 14 , 2008 ), pp . 386 - 397 , XP022540464 . Kumar et al . , “ Nestorone : a progestin with a unique pharmacologi European Examination Report for Application No . 10768168 .6 cal profile ” , Steroids 65 (2000 ) 629 -636 . dated Apr. 18 , 2013 . Liu et al ., " Progesterone increases rat neural progenitor cell cycle Liu et al, “ Clinically Relevant Progestins Regulate Neurogenic and gene expression and proliferation via exracellularly regulated kinase Neuroprotective Responses in Vitro and in Vivo ” , Endocrinology , and progesterone receptor membrane components 1 and 2 ” , vol. 151 , No . 12 , Dec . 1 , 2010 (Dec . 1 , 2010 ) , pp . 5782 - 5794 , Neuroendocrinology, Jul. 2009 , 15 ( 7 ) :3186 -3196 . xP008131261. Wang et al ., “ Regenerative potential of allopregnanolone” , Brain Reserach Reviews, 57 (2008 ) , pp . 398 -409 . * cited by examiner U . S . 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
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