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Ep 2723384 B1 (19) TZZ ¥¥_T (11) EP 2 723 384 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 47/00 (2006.01) A61P 25/28 (2006.01) 29.08.2018 Bulletin 2018/35 G01N 33/573 (2006.01) (21) Application number: 12802206.8 (86) International application number: PCT/US2012/043732 (22) Date of filing: 22.06.2012 (87) International publication number: WO 2012/177997 (27.12.2012 Gazette 2012/52) (54) TREATMENT OF PROTEINOPATHIES BEHANDLUNG VON PROTEINOPATHIEN TRAITEMENT DE PROTÉINOPATHIES (84) Designated Contracting States: • JOSEPH R MAZZULLI ET AL: "Gaucher Disease AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Glucocerebrosidase and -Synuclein Form a GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Bidirectional Pathogenic Loop in PL PT RO RS SE SI SK SM TR Synucleinopathies",CELL, CELL PRESS, US, vol. 146, no. 1, 23 June 2011 (2011-06-23) , pages (30) Priority: 22.06.2011 US 201161499930 P 37-52, XP028100083, ISSN: 0092-8674, DOI: 10.1016/J.CELL.2011.06.001 [retrieved on (43) Date of publication of application: 2011-06-07] 30.04.2014 Bulletin 2014/18 • SEANCLARK ET AL: "Improved pharmacological chaperones for the treatment of neuronopathic (73) Proprietor: The General Hospital Corporation Gaucher and Parkinson’s disease", Boston, MA 02114 (US) MOLECULAR GENETICS AND METABOLISM, vol. 102, 15 January 2011 (2011-01-15), page S12, (72) Inventors: XP055176973, DOI: 10.1016/j.ymgme.2010.11.039 • KRAINC, Dmitri • SAMARJIT PATNAIK ET AL: "Discovery, Boston, Massachusetts 02109 (US) Structure-Activity Relationship, and Biological • MAZZULLI, Joseph, R. Evaluation of Noninhibitory Small Molecule Boston, Massachusetts 02113 (US) Chaperones of Glucocerebrosidase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 12, 30 (74) Representative: Kehoe, Laura Ellen May 2012 (2012-05-30), pages 5734-5748, Keltie LLP XP055140348, ISSN: 0022-2623, DOI: No.1 London Bridge 10.1021/jm300063b London SE1 9BA (GB) • COOPER A A ET AL: "[alpha]-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in (56) References cited: Parkinson’s models", SCIENCE, AMERICAN WO-A1-2008/144773 WO-A1-2012/078855 ASSOCIATION FOR THE ADVANCEMENT OF WO-A2-2007/012061 WO-A2-2007/140212 SCIENCE, US, vol. 313, no. 5785, 21 July 2006 EA-B1- 013 752 US-A1- 2010 113 358 (2006-07-21), pages324-328, XP002536146, ISSN: 0036-8075, DOI: 10.1126/SCIENCE.1129462 [retrieved on 2006-06-22] • MICHAEL J.DEVINE ET AL: "Parkinson’sdisease and [alpha]-synuclein expression", MOVEMENT DISORDERS, vol. 26, no. 12, 1 September 2011 (2011-09-01), pages 2160-2168, XP055176859, ISSN: 0885-3185, DOI: 10.1002/mds.23948 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 723 384 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 723 384 B1 • MARIA DO ROSÁRIO ALMEIDA: • ’Proteostasis Therapeutics Exclusively Licenses "Glucocerebrosidase Involvement in Parkinson Discoveries Related to Unfolded Protein Disease and Other Synucleinopathies", Response from Ron Laboratory at New York FRONTIERS IN NEUROLOGY, vol. 3, 1 January University’ PROTEOSTASIS THERAPEUTICS 07 2012 (2012-01-01), XP055176789, ISSN: January 2010, XP055140247 Retrieved from the 1664-2295, DOI: 10.3389/fneur.2012.00065 Internet: • EHUD GOLDIN ET AL: "High Throughput <URL:http://www.proteostasis.com/news_event Screening for Small Molecule Therapy for s/pr_2010_01_07.php> [retrieved on 2012-08-31] Gaucher Disease Using Patient Tissue as the • CLARK JOANNE ET AL.: ’Oral N-acetyl-cysteine Source of Mutant Glucocerebrosidase", PLOS attenuates loss of dopaminergic terminals in ONE, vol. 7, no. 1, 17 January 2012 (2012-01-17), alpha-synuclein overexpressing mice’ PLOS page e29861, XP055176689, DOI: ONE vol. 5, no. 8, 23 August 2010, page E12333, 10.1371/journal.pone.0029861 XP055140250 Retrieved from the Internet: • COOKSON, M.R.: ’alpha-Synuclein and neuronal <URL:http://www.plosone.org/article/info%3A cell death’ MOLECULAR doi%2F 10.1371%2Fjournal.pone.0012333> NEURODEGENERATIONvol. 4, no. 9, 04 February [retrieved on 2012-09-06] 2009, page 8, XP021052340 Retrieved from the • CASTRO-OBREGON, SUSANA LYSOSOMES, Internet: AUTOPHAGY | LEARN SCIENCE AT SCITABLE <URL:http://www.molecularneurodegeneration. vol. 3, no. 9, 2010, page 49, XP055140254 com/content/4/1/9> [retrieved on 2012-08-31] Retrieved from the Internet: • ’Bolshaya meditsinskaya entsiklopediya’ <URL:http://www.nature.com/scitable/topicpa IZDANIE TRETIE. MOSKVA, (SOVETSKAYA ge/the-discovery-of-lysosomes-and-autophagy ENTSIKLOPEDIYA) vol. 13, 1980, pages 179 - 181, -14199828> [retrieved on 2012-09-10] XP008172691 • WINSLOW, ASHLEY R. ET AL.: ’alpha-Synuclein impairs macroautophagy: implications for Parkinson’s disease’ J CELL BIOL. vol. 190, no. 6, 2010, pages 1023 - 1037, XP055140237 • TATTI, MASSIMO ET AL.: ’Autophagy in Gaucher disease due to saposin C deficiency’ AUTOPHAGY vol. 7, no. 1, January 2011, pages 94 - 95, XP055140241 2 EP 2 723 384 B1 Description Background 5 [0001] Proteinopathies are diseases, disorders, and/or conditions associated with abnormalities in the production, folding, aggregation, metabolism, or degradation of proteins. Typically, proteinopathies are associated with and/or char- acterized by accumulation of one or more particular proteins into aggregates. Protein aggregates are observed in a variety of different types of diseases, disorders, and/or conditions, including cognitive impairment disorders, proliferative diseases, inflammatory diseases, cardiovascular diseases, immunologic diseases, ocular diseases, mitochondrial dis- 10 eases, neurodegenerative diseases, and lysosomal storage diseases. WO 2012/078855 A1 and Patnaik et al. (Med. Chem.; 55; 5734-5748) relate to substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and the use of these compounds in treating lysosolmal storage disorders such as Gau- cher disease. 15 Clark et al (Mol. Gen. Metabol.; 102; S12; 2011) relates to improved pharmacological chaperones for the treatment of neuronopathic Gaucher and Parkinson’s disease. This document refers to a certain compound known from WO 2007/140212 A2 and WO 2008/144773 A1, that generally links synucleinopathy with GCase activity. 20 Cooper et al. (Science; 313; 324-328, 2006) generally describes alpha-synucein (aSyn) misfolding being associated with neurodegenerative disorders such as Parkinson’s disease. This document does not describe any involvement of GCase. Devine et al. (Movement Disorders; 26; 2160-2168, 2011) and Do Rosario Almeida (Frontiers in Neurology; 2; 65, 25 2012) describe the relation between Parkinson’s disease and synucleinopathy. WO 2007/012061 A2 relates to the use of antibodies that increase the lysosomal activity from the treatment of synucleinopatic disease, such as Parkinson’s disease. The antibodies of WO 2007/012061 A2 do not bind directly to a lysosomal enzyme. 30 Goldin et al. (PLoS ONE 7; e29861; 2012) describes the compound NCGC00182186 as a chaperone for GCase. Goldin suggests that NCGC00182186 may be suitable for the treatment of Gaucher disease. Summary 35 [0002] The present invention relates to the finding that activation of lysosomal enzymes, through increased levels and/or increased activity, can provide effective treatment for, and even prophylaxis of, certain proteinopathies. For example, the present invention provides novel insights into lysosomal activity and its effects on protein aggregation, and demonstrates that biochemical pathways linked to lysosomal function regulate levels of protein aggregation in various 40 contexts, specifically including various cell cultures (including both neuronal and non-neuronal cultures), mammalian organisms (e.g., mice), and human brain. The present invention specifically relates to the insight that, in some instances, increased trafficking of lysosomal enzymes can provide effective treatment (and/or prophylaxis) of certain proteinopa- thies. [0003] The present invention relates to the specific and surprising finding that, in some embodiments, increasing level 45 and/or activity of lysosomal enzymes can provide effective treatment of, and in some embodiments prophylaxis of, proteinopathies other than lysosomal storage diseases. The present invention teaches particularly that increasing level and/or activity of lysosomal enzymes can provide effective treatment of, and in some embodiments prophylaxis of, certain neurodegenerative diseases, disorders, and/or conditions. In some particular embodiments, the present invention dem- onstrates that increasing level and/or activity of lysosomal enzymes can provide effective treatment of, and in some 50 embodiments prophylaxis of, Parkinson’s Disease. [0004] The present invention relates to the particular finding that increasing level and/or activity of lysosomal enzyme, glucocerebrosidase (GCase), can provide effective treatment, and even prophylaxis of, certain proteinopathies. [0005] The present invention relates to the particular finding that increasing lysosomal degradation capacity can provide effective treatment for, and even prophylaxis of, certain proteinopathies. 55 [0006] As described herein, activating GCase activity in brain cells reduces α-synuclein levels in those cells. Suitably, activation of GCase
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