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Wo 2010/117727 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 14 October 2010 (14.10.2010) WO 2010/117727 A2 (51) International Patent Classification: TECHNOLOGY TRANSFER, NATIONAL INSTI¬ A61K 31/407 (2006.01) A61K 31/7105 (2006.01) TUTES OF HEALTH [US/US]; 601 1 Executive Boule A61K 31/40 (2006.01) A61K 31/711 (2006.01) vard, Ste 325, MSC 7660, Bethesda, Maryland A61K 38/16 (2006.01) A61P 25/00 (2006.01) 20892-7660 (US). (21) International Application Number: (72) Inventors; and PCT/US2010/029056 (75) Inventors/Applicants (for US only): ROGERS, Jack [USAJS]; 63 Sunnyside Ave., Arlington, Massachusetts (22) International Filing Date: 02474 (US). TANZI, Rudolph E. [US/US]; 3 Oceanside 29 March 2010 (29.03.2010) Drive, Hull, Massachusetts 02045 (US). MOIR, Robert (25) Filing Language: English [US/US]; 6 1 Tilden Rd, Scituate, Massachusetts 02066 (US). GREIG, Nigel [US/US]; 11 Anne Brent Garth, (26) Publication Language: English Phoenix, Maryland 2 113 1 (US). FRIEDLICH, Avi L. (30) Priority Data: [US/US]; 8 Dwyer Circle, Medford, Massachusetts 02155 61/164,729 30 March 2009 (30.03.2009) US (US). (71) Applicants (for all designated States except US): THE (74) Agents: KUGLER DEYOUNG, Janice et al; Fish & GENERAL HOSPITAL CORPORATION [US/US]; Richardson P.C , P.O. Box 1022, Minneapolis, Minnesota 55 Fruit Street, Boston, Massachusetts 021 14 (US). NA¬ 55440-1022 (US). TIONAL INSTITUTE OF AGING OFFICE OF [Continued on next page] (54) Title: PHENSERINE AND POSIPHEN FOR TREATING NEUROP SYCHIATRIC AND NEURODEGENERATIVE CON DITIONS Figure IA (57) Abstract: Described are methods for treating synucle- inopathy in a subject, by administering to the subject a ther 453 Abha-Syn apeutically effective dose of one or both of POSIPHEN and phenserine. 4OD Ϊ O0 S3 0 1 1 10 0 1 1 S i O (µM) eti ri n ϊ pherp O N -* Figure 1C (81) Designated States (unless otherwise indicated, for every GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, kind of national protection available): AE, AG, AL, AM, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ML, MR, NE, SN, TD, TG). ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, Published: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, — without international search report and to be republished TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. upon receipt of that report (Rule 48.2(g)) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, PHENSERINE AND PQSIPHEN FOR TREATING NEURQPSYCHIATRIC AND NEURODEGENERATIVE CONDITIONS CLAIM OF PRIORITY This application claims the benefit of U.S. Provisional Patent Application Serial No. 61/164,729, filed on March 30, 2009, the entire contents of which are incorporated by reference herein. FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant Nos. NS10874 and NS059434 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD This invention relates to novel uses for phenserine [(-)-phenserine tartrate] and POSIPHEN [(+)-phenserine tartrate], particularly for the treatment of neuropsychiatric conditions associated with production of alpha-synuclein protein. BACKGROUND Phenserine, and its positive stereoisomer POSIPHEN, are presently in clinical assessment for Alzheimer's disease (AD) as blockers of amyloid precursor protein translation (anti-amyloid) (see, e.g., ClinicalTrials.gov Identifier: NCT01072812). The drugs have been well-tolerated in Phase I trials. SUMMARY An inter-relationship exists between the Parkinson's disease causative protein, alpha-synuclein, and the Alzheimer's Aβ-amyloid plaque protein. Phenserine reached clinical assessment for AD as an anticholinesterase and blocker of amyloid precursor protein (APP) translation. As demonstrated herein, this well-tolerated compound also reduced neural alpha-synuclein expression over a similar dose range as APP. POSIPHEN, a (+) stereoisomer of phenserine that has no anticholinesterase activity, has also shown a capacity to lower alpha-synuclein expression. Thus in one aspect, the invention provides methods for treating a synucleinopathy in a subject. The methods include identifying a subject having a synucleinopathy; selecting the subject on the basis that they have a synucleinopathy; and administering to the subject a therapeutically effective dose of one or both of POSIPHEN and phenserine. In some embodiments, the synucleinopathy is selected from the group consisting of spectrum neurodegenerative diseases associated with aberrant production of alpha-synuclein (e.g., Parkinson's disease, dementia with Lewy bodies, Lewy body variant of Alzheimer's disease, multiple system atrophy, Parkinsonism dementia of Guam, and neurodegeneration with brain iron accumulation type I) and spectrum neuropsychiatric disorders associated with aberrant production of alpha- synuclein (e.g., REM sleep behavioral disorders, alcohol and cocaine dependence, and anxiety disorders). In some embodiments, the methods include administering to the subject a therapeutically effective dose of POSIPHEN. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG. IA is a pair of line graphs illustrating the effect of treatment with phenserine or POSIPHEN™ on levels of α-synuclein (lower lines) or amyloid precursor protein (APP), relative to an actin standard. FIG. IB is the structure of (-)-phenserine. FIG. 1C is the structure of (+)-POSIPHEN. FIG. 2 is a schematic of a luciferase reporter construct (top) and a bar graph showing the effect of APP Blocker #9, Phenserine, and POSIPHEN on expression of the reporter construct. FIG. 3 is a pair of schematics showing a luciferase reporter constructs with (left) and without (right) an alpha-synuclein 5'UTR sequence, and two bar graphs showing the effects of APP Blocker #9, Phenserine, and POSIPHEN on expression of the two constructs in H2A cells (left) and H4-pGL3 cells (right). DETAILED DESCRIPTION Described herein are methods of treating subjects suffering from disorders associated with aberrant production of alpha-synuclein, e.g., neuropsychiatric and neurodegenerative disorders. The methods include identifying a subject in need of such treatment, e.g., on the basis that they are suffering from a disorder associated with production of alpha-synuclein, and administering a therapeutically effective amount of the (-) isomer phenserine or the (+) isomer POSIPHEN™. The methods can further include monitoring the subject for an improvement in one or more parameters of their condition, e.g., a measure of cognitive impairment or function. a-Synuclein α-synuclein (α-syn) is an approximately 15 kd protein expressed from the SNCA gene on Chromosome 4 (at 4q21). The official name is synuclein, alpha (non A4 component of amyloid precursor). See, e.g., GenelD: 6622. There are two isoforms in humans, including alpha-synuclein isoform NACP 140 (mRNA: nCBI Ace. No. NM_000345.2, protein: NP_000336.1) and alpha-synuclein isoform NACP112 (mRNA: NM_007308.1 protein: NP_009292.1). The NACP140 variant is the longer transcript and encodes a longer isoform than the NACPl 12 variant, which lacks an alternate in-frame segment, compared to variant NACP 140, resulting in a shorter protein that has a distinct C-terminus, compared to isoform NACP 140. The genomic sequence is available atNC_000004.10 (nt 90977156-90865728, complement). Information regarding α-synuclein in other species is available in the Gene database, e.g., at GenelD Nos. 20617 (Mus musculus); 29219 (Rattus norvegicus); 641350 (Sus scrofa); 706985 (Macaca mulata); 395393 (Gallus gallus); and 393397 (Danio rerio). As previously described (Friedlich et al., MoI Psychiatry. 12(3):222-3 (2007); USPTO 20080003570), alpha synuclein is regulated at the post-transcriptional level through a translation enhancer element in its mRNA 5' untranslated region. This translational enhancer may be targeted for drug discovery to modulate expression of alpha synuclein protein levels. As one theory, not meant to be limiting, this translational enhancer may be successfully targeted by phenserine and POSIPHEN. Neuropsychiatry
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