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Ep 3006040 A1 (19) TZZ¥ZZZZ_T (11) EP 3 006 040 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 13.04.2016 Bulletin 2016/15 A61K 38/50 (2006.01) A61K 38/45 (2006.01) A61K 31/7084 (2006.01) C07H 19/20 (2006.01) (2006.01) (2006.01) (21) Application number: 15193068.2 A61K 48/00 C12N 9/12 (22) Date of filing: 03.06.2005 (84) Designated Contracting States: • ARAKI, Toshiyuki AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Kodaira, Tokyo 187-0031 (JP) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR • SASAKI, Yo St. Louis, MO 63144 (US) (30) Priority: 04.06.2004 US 577233 P 04.01.2005 US 641330 P (74) Representative: Smaggasgale, Gillian Helen WP Thompson (62) Document number(s) of the earlier application(s) in 138 Fetter Lane accordance with Art. 76 EPC: London EC4A 1BT (GB) 05790283.5 / 1 755 391 Remarks: (71) Applicant: Washington University This applicationwas filed on 4.11.2015 as a divisional Saint Louis, MO 63130 (US) application to the application mentioned under INID code 62. (72) Inventors: • MILBRANDT, Jeffrey St. Louis, MO 63105 (US) (54) METHODS AND COMPOSITIONS FOR TREATING NEUROPATHIES (57) Methods of treating or preventing axonal degra- dation in neuropathic diseases in mammals are dis- closed. The methods can comprise administering to the mammal an effective amount of an agent that acts by increasing sirtuin activity in diseased and/or injured neu- rons. The methods can also comprise administering to the mammal an effective amount of an agent that acts by increasing NAD activity in diseased and/or injured neurons.Also disclosed aremethods of screening agents for treating a neuropathies and recombinant vectors for treating or preventing neuropathies. EP 3 006 040 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 006 040 A1 2 Description SIRT1. The activation of SIRT1 results in a decrease in severity of axonal degeneration or a prevention of axonal GOVERNMENT INTERESTS degeneration. It is also believed possible that the in- crease in NAD activity could act through other mecha- [0001] This work was supported at least in part with 5 nisms not involving sirtuin. Thus, increasing NAD activity, funds from the federal government under U.S.P.H.S. which may act through increasing SIRT1 activity or 5RO1 NS40745. The U.S. Government may have certain through one or more other mechanisms or both can di- rights in the invention. minish or prevent axonal degeneration in injured mam- malian axons. RELATED APPLICATION DATA 10 [0006] Thus, in various embodiments, the present in- vention is directed to a method of treating or preventing [0002] This application claims benefit under 35 U.S.C. a neuropathy in a mammal and, in particular, in a human § 119(e) to United States Provisional Application Serial in need thereof. The method can comprise administering No. 60/577,233, filed June 4, 2004 and United States an effective amount of an agent that acts to increase Provisional Application Serial No. 60/641,330, filed Jan- 15 sirtuin activity and, in particular, SIRT1 activity in dis- uary 4,2005. These applications are incorporated herein eased and/or injured neurons. in their entireties by reference. [0007] In various embodiments, the agent can in- crease SIRT1 activity through increasing NAD activity. It FIELD is believed that increasing NAD activity can increase sir- 20 tuin activity because NAD can act as a substrate of [0003] This invention relates generally to diseases and SIRT1. Such agents can include NAD or NADH, a pre- conditions involving neurons and, more particularly, to cursor of NAD, an intermediate in the NAD salvage path- methodsand compositions for treatingor preventingneu- way or a substance that generates NAD such as a nico- ropathies and other diseases and conditions involving tinamide mononucleotide adenylyltransferase (NMNAT) neurodegeneration. Also included are methods of iden- 25 or a nucleic acid encoding a nicotinamide mononucle- tifying agents for treating or preventing neuropathies. otide adenylyltransferase. The nicotinamide mononucle- otide adenylyltransferase can be an NMNAT1 protein. BACKGROUND [0008] In various embodiments, the agent can also act to directly increase SIRT1 activity and as such, the agent [0004] Axon degeneration occurs in a variety of neu- 30 can be a sirtuin polypeptide or a nucleic acid encoding a rodegenerative diseases such as Parkinson’s and Alzhe- sirtuin polypeptide or a substance such as a stilbene, a imer’s diseases as well as upon traumatic, toxic or chalcone, a flavone, an isoflavanone, a flavanone or a ischemicinjury to neurons. Such diseases and conditions catechin. Such compounds can include a stilbene select- are associated with axonopathies including axonal dys- ed from the group consisting of resveratrol, piceatannol, function. One example of axonopathy is Wallerian de- 35 deoxyrhapontin, trans-stilbene and rhapontin; a chal- generation (Waller, Philos Trans R. soc. Lond. cone selected from the group consisting of butein, isoli- 140:423-429,1850), whichoccurs when the distal portion quiritigen and 3,4,2’,4’,6’-pentahydroxychalcone; a fla- of the axon is severed from the cell body. The severed vone selected from the group consisting of fisetin, axon rapidly succumbs to degeneration. Axonopathy 5,7,3’,4’,5’-pentahydroxyflavone, luteolin, 3,6,3’,4’-tet- can, therefore, be a critical feature of neuropathic dis- 40 rahydroxyflavone, quercetin, 7,3’,4’,5’-tetrahydroxyfla- eases and conditions and axonal deficits can be an im- vone, kaempferol, 6-hydroxyapigenin, apigenin, portant component of the patient’s disability. 3,6,2’,4’-tetrahydroxyflavone, 7,4’-dihydroxyflavone, 7,8,3’,4’-tetrahydroxyflavone, 3,6,2’,3’-tetrahydroxyfla- SUMMARY vone, 4’-hydroxyflavone, 5,4’-dihydroxyflavone, 5,7-di- 45 hydroxyflavone, morin, flavone and 5-hydroxyflavone; an [0005] Accordingly, the present inventors have suc- isoflavone selected from the group consisting of daidzein ceeded in discovering that axonal degeneration can be and genistein; a flavanone selected from the group con- diminished or prevented by increasing NAD activity in sisting of naringenin, 3,5,7,3’,4’-pentahydroxyflavanone, diseased and/or injured neurons. It is believed that the and flavanone or a catechin selected from the group con- increased NAD activity can act to increase sirtuin activity 50 sisting of (-)-epicatechin, (-)-catechin, (-)-gallocatechin, which then produces a decrease in axonal degeneration (+)-catechin and (+)-epicatechin. of injured neuronal cells. Thus, one approach to prevent- [0009] In various embodiments, the invention can also ing axonal degeneration can be by activating sirtuin mol- involve methods of treating a neuropathy by administer- ecules, i.e. SIRT1 in injured mammalian axons. The ac- ing to a mammal and, in particular, a human, an effective tivation of SIRT1 can be through direct action on the55 amount of an agent that acts by increasing nuclear NAD SIRT1 molecule or by increasing the supply of nicotina- activity in diseased and/or injured neurons and/or sup- mide adenine dinucleotide (NAD) which acts as a sub- porting cells such as, for example, glia, muscle cells, fi- strate for the histone/protein deacetylase activity of broblasts, etc. 2 3 EP 3 006 040 A1 4 [0010] Such agent can be NAD or NADH, nicotinamide activity can be an increase in nuclear NAD activity. mononucleotide, nicotinic acid mononucleotide or nico- [0015] Methods are also provided for screening agents tinamide riboside or derivatives thereof; or an enzyme that increase sirtuin activity in neurons as well as for that generates NAD such as a nicotinamide mononucle- screening agents that increase NAD biosynthetic activity otide adenylyltransferase or a nucleic acid encoding an 5 in neurons. The methods can comprise administering to enzyme that generates NAD such as a nucleic acid en- mammalian neuronal cells in vitro or in vivo a candidate coding a nicotinamide mononucleotide adenylyltrans- agent, producing an axonal injury to the neuronal cells ferase or an agent that increases expression of a nucleic and detecting a decrease in axonal degeneration of the acid encoding an enzyme in a pathway that generates injured neuronal cells. Such methods can in some em- NAD or an agent that increases activity and/or stability 10 bodiments be primary screening methods in which sec- of an enzyme in a pathway that generates NAD or an ondary assays further delineate activity as associated agent that increases NAD activity. The nicotinamide with sirtuin activity or with NAD and enzymes or compo- mononucleotide adenylyltransferase can be an NMNAT1 nents of NAD biosynthetic or salvage pathways. protein. [0016] In various embodiments of the screening meth- [0011] In various embodiments, the invention can also 15 ods of the present invention, axonal injury can be pro- involve methods of treating or preventing an optic neu- duced by a number of methods including chemically in- ropathy in a mammal in need thereof. The methods can juring the neuronal cells, thermally injuring the neuronal comprise administering to the mammal an effective cells, oxygen-depriving the neuronal cells, and physically amount of an agent that acts by increasing NAD activity injuring the neuronal cells. in diseased and/or injured neurons. Administering to the 20 [0017] A recombinant vector is also provided in various mammal can comprise administering to the eye, in par- embodiments. The vector can comprise a promoter op- ticular by administering the agent with a sustained re- eratively linked to a sequence encoding a mammalian lease delivery system or by administering a sustain re- NMNAT1 protein or NMNAT3 protein. In various aspects lease pellet comprising the agent to the eye. of such embodiments, the recombinant vector can be a [0012] The agent can be NAD or NADH, nicotinamide 25 lentivirus or an adeno-associated virus. mononucleotide, nicotinic acid mononucleotide or nico- [0018] Also provided in various embodiments, is a re- tinamide riboside; or an enzyme that generates NAD combinant vector comprising a promoter operatively such as a nicotinamide mononucleotide adenylyltrans- linked toa sequence encoding a SIRT1 protein.
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