WO2019067587A1 - USE OF METFORMIN AND ANALOGUES THEREOF TO REDUCE RAN PROTEIN RATES DURING TREATMENT OF NEUROLOGICAL DISORDERS - Google Patents

USE OF METFORMIN AND ANALOGUES THEREOF TO REDUCE RAN PROTEIN RATES DURING TREATMENT OF NEUROLOGICAL DISORDERS Download PDF

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WO2019067587A1
WO2019067587A1 PCT/US2018/052913 US2018052913W WO2019067587A1 WO 2019067587 A1 WO2019067587 A1 WO 2019067587A1 US 2018052913 W US2018052913 W US 2018052913W WO 2019067587 A1 WO2019067587 A1 WO 2019067587A1
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certain embodiments
optionally substituted
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compound
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French (fr)
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Laura Ranum
Tao Zu
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University of Florida
University of Florida Research Foundation Inc
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University of Florida Research Foundation Inc
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Priority to AU2018342105A priority patent/AU2018342105B2/en
Priority to US16/650,721 priority patent/US11903910B2/en
Priority to JP2020517472A priority patent/JP7350337B2/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/11—Protein-serine/threonine kinases (2.7.11)
    • C12Y207/11001—Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders

Definitions

  • Mutations of certain repeat expansions are associated with a number of different neurological diseases (e.g. , C90RFf72 amyotrophic lateral sclerosis (ALS), or C90RFf72 frontotemporal dementia; myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2); spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, 31, and 36; spinal bulbar muscular atrophy;
  • ALS amyotrophic lateral sclerosis
  • DM2 myotonic dystrophy type 2
  • spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, 31, and 36 spinal bulbar muscular atrophy
  • DPLA dentatorubral-pallidoluysian atrophy
  • HD Huntington' s disease
  • FXTAS Fragile X Tremor Ataxia Syndrome
  • Fuch' s endothelial corneal dystrophy FECD
  • RAN proteins four repeat associated non-ATG translation proteins (also referred to as RAN proteins) - polyalanine, polyserine, polyleucine, and polycysteine (polyAla, polySer, polyLeu and polyCys, respectively)-accumulate in the brains, tissue (e.g. , blood, cerebrospinal fluid), and central nervous systems of subjects having Huntington's disease (HD).
  • RAN proteins with dipeptide RAN proteins (e.g. , polyGlyPro (GP), polyGlyAla (GA), polyGlyArg (GR), polyProAla (PA)) have been shown to accumulate in patient brains, blood and other tissues.
  • GP polyGlyPro
  • GA polyGlyAla
  • GR polyGlyArg
  • PA polyProAla
  • RAN proteins can be detected in a biological sample (e.g., blood, serum, tissue, or cerebrospinal fluid (CSF)) from a subject having or at risk of developing HD, C90RF72 ALS, C90RF72 FTD, DM1, DM2, FXTAS, SCA8; Huntington's disease-like 2 syndrome (HDL2); Fragile X syndrome (FXS); disorders related to 7pl l .2 folate- sensitive fragile site FRA7A; disorders related to folate- sensitive fragile site 2ql l FRA2A; and Fragile XE syndrome (FRAXE); or other diseases caused by micro satellite repeat expansion mutations.
  • a biological sample e.g., blood, serum, tissue, or cerebrospinal fluid (CSF)
  • CSF cerebrospinal fluid
  • ⁇ - ⁇ is intended to encompass Ci, C 2 , C 3 , C 4 , Cs, C 6 , Ci-6, Ci-5, Ci ⁇ , Ci- 3 , Ci- 2 , C 2 -6, C2-5, C2- , C2-3, C3-6, C3-5, C 3 ⁇ , C4-6, C4-5, and C5-6.
  • the hydrocarbon chain is substituted (e.g. , -CH(C 2 Hs)- and -CF 2 -). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“O-io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”).
  • an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("Ci ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some
  • an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl").
  • an alkenyl group has 2 carbon atoms ("C2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2 ⁇ alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like.
  • alkynyl examples include heptynyl (C 7 ), octynyl (C 8 ), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents.
  • the alkynyl group is unsubstituted C2-10 alkynyl.
  • the alkynyl group is substituted C2-10 alkynyl.
  • a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl").
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is unsubstituted C3-10 carbocyclyl.
  • the carbocyclyl group is a substituted C3-10 carbocyclyl.
  • a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl").
  • C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5).
  • C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C 4 ).
  • Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-10 cycloalkyl.
  • the cycloalkyl group is substituted C3-10 cycloalkyl.
  • Heterocyclyl or “heterocyclic” refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5- membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl").
  • an aryl group has six ring carbon atoms ("C6 aryl”; e.g., phenyl).
  • bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups are further referred to using the suffix -ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted” or “unsubstituted” alkyl, "substituted” or
  • substituted carbocyclyl, "substituted” or “unsubstituted” heterocyclyl, "substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group).
  • substituted whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • each instance of is, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkyl, alkynyl, heteroCi-10 alkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered hetero
  • each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R xl groups taken together form a 5- to 6-membered heterocyclic ring.
  • Alkoxy or "alkoxyl” refers to a radical of the formula: -O-alkyl.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR 2121 , -N(R CC ) 2 , -CN,
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • TBOC l-methyl-l-(4-biphenylyl)ethyl carbamate
  • Bpoc l-(3,5-di-t-butylphenyl)-l- methylethyl carbamate
  • Pyoc 2-(2'- and 4'-pyridyl)ethyl carbamate
  • 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate i-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carb
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl- 3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l, l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl- l,3,5-triazacyclohexan-2-one, 5-
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl,
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • LG is an art-understood term referring to a molecular fragment that departs with a pair of electrons in a heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group.
  • the leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfur-containing moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl) 4 " salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • Compounds described herein, including, for example, metformin may be prepared, e.g. , in crystalline form, and may be solvated. Suitable solvates include
  • solvates and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • Solvate encompasses both solution-phase and isolable solvates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H 2 0, wherein R is the compound and wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g. , monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g.
  • Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g. , primates (e.g. , cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g.
  • humans i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals
  • prophylactically effective amount is effective for preventing a neurological disease associated with repeat expansions. In certain embodiments, a prophylactic ally effective amount is effective for preventing a neurological disease associated with RAN protein accumulation. In certain embodiments, a prophylactically effective amount is effective for preventing a neurodegenerative disease associated with repeat expansions.
  • a prophylactically effective amount is effective in preventing the accumulation of RAN proteins in tissues from subjects with gene mutation
  • FXTAS Huntington's disease-like 2 syndrome
  • HDL2 Huntington's disease-like 2 syndrome
  • FXS Fragile X syndrome
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g.
  • amino acids in an inventive protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification.
  • a protein may also be a single molecule or may be a multi-molecular complex.
  • a protein may be a fragment of a naturally occurring protein or peptide.
  • a protein may be naturally occurring, recombinant, or synthetic, or any combination of these.
  • a "RAN protein (repeat- associated non-ATG translated protein)” is a polypeptide translated from sense or antisense RNA sequences carrying a nucleotide expansion without the requirement for an AUG initiation codon.
  • RAN proteins comprise "expansion repeats" or "repeat expansions" of an amino acid, termed poly amino acid repeats. For example, ' 'AAA A A A A A A A A A A A A A A A A A A A' ' (poly-Alanine) (SEQ ID NO: 1),
  • LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL (poly-Leucine) (SEQ ID NO: 2), “SSSSSSSSSSSSSSSSSSSS” (poly-Serine) (SEQ ID NO: 3), or “CCCCCCCCCCCCCCCCCC” (poly-Cysteine) (SEQ ID NO: 4) are poly amino acid repeats that are each 20 amino acid residues in length.
  • RAN proteins can have a poly amino acid repeat of at least 25, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, or at least 200 amino acid residues in length. In some embodiments, a RAN protein has a poly amino acid repeat more than 200 amino acid residues in length.
  • RAN proteins are translated from abnormal repeat expansions (e.g., CAG repeats) of DNA.
  • RAN proteins comprise expansion repeats of one or amino acid, termed poly amino acid repeats (e.g., di-amino acid repeats).
  • RAN protein accumulation e.g., in the nucleus or cytoplasm of a cell disrupts cellular function and induces cellular toxicity.
  • translation and accumulation of RAN proteins is associated with a disease, for example, a neurological disease, neurodegenerative disease, or neurodegenerative disorder.
  • diseases associated with RAN protein translation and accumulation include but are not limited to C90RFf72 ALS, C90RFf72 FTD, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, 31, and 36; spinal bulbar muscular atrophy; dentatorubral-pallidoluysian atrophy (DRPLA); Huntington's disease (HD); Fuch's endothelial corneal dystrophy (FECD); Fragile X Tremor Ataxia Syndrome (FXTAS); Huntington's disease-like 2 syndrome (HDL2); Fragile X syndrome (FXS); disorders related to 7pl l.2 folate- sensitive fragile site FRA7A; disorders related to folate- sensitive fragile site 2ql l FRA2A
  • a “repeat expansion” is a mutation which increases the number of times that a short nucleotide sequence is repeated. Exemplary repeat expansions are provided above in the definition of "RAN protein.”
  • C90RFf72 amyotrophic lateral sclerosis or “C90RFf72 ALS” refers to
  • C90RFJ72 amyotrophic lateral sclerosis associated with a hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C90RFJ72) gene.
  • C90RFf72 frontotemporal dementia or “C90RFf72 FTD” refers to frontotemporal dementia associated with a hexanucleotide expansion mutation in the C90RFJ72 gene.
  • neurodegenerative diseases refer to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system).
  • Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells. Examples of neurodegenerative diseases include but are not limited to C90RFf72 ALS, C90RFf72 FTD, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, 31, and 36; spinal bulbar muscular atrophy;
  • Neuromuscular diseases refer to a type of neurological disease marked by pathologies of the nerves or neuromuscular junctions.
  • Exemplary neuromuscular diseases include but are not limited to amyotrophic lateral sclerosis, multiple sclerosis, and spinal muscular atrophy.
  • constructs contain epitope tags that are incorporated into the C-terminal regions of the ATG-initiated poly-Gin and non-ATG initiated RAN proteins (poly-Gin, poly-Leu-Pro- Ala- Cys and poly-Gly-Pro) which are expressed across these repeat expansions.
  • the lane labeled CCTG expresses the following RAN proteins: LP AC -Flag, LPAC-HA, and LPAC-Myc.
  • the lane labeled G4C2 is designed to detect the following RAN proteins: GP-Flag, GR-HA, and GA-Myc.
  • FIGs. 3A-3J show metformin inhibits PKR and reduces RAN proteins and ameliorates disease in C9orf72 ALS/FTD BAC transgenic mice (C9-BAC) mice.
  • FIG. 3A shows a protein blot indicating that metformin reduces RAN protein expression in HEK293T cells transiently transfected with CAG, CCTG, CAGG, and G4C2 expansion constructs.
  • FIG. 3B shows data indicating that metformin reduces levels of p-PKR (T446 and T451) in cells transfected with repeat expansion constructs.
  • FIG. 3C is a schematic diagram showing the study design for two metformin treatment groups, with treatment at 5 mM metformin from 2 to 5 months of age or from six to 9 months of age.
  • FIG. 3D shows data quantifying GA aggregates and indicates a reduction in GA aggregates in mice treated with 5 mM metformin in their drinking water from 2-5 months compared to untreated C9-500 mice.
  • FIG. 3E shows quantification of GFAP staining, indicating decreased levels of reactive gliosis in C9-500 metformin treated mice compared to C9-500 control animals.
  • FIG. 3F shows DigiGait analyses indicating that of eight parameters that differed between untreated C9-500 and NT controls, 6 of these parameters improved in C9-500 animals treated with metformin.
  • FIG. 3G shows open field analyses showing decreased center time in C9-500 animals that is normalized in C9-500 animals treated with metformin.
  • FIG. 3H shows data from MSD assays indicating soluble GP levels are reduced in C9-500 animals treated with metformin compared to C9-500 controls.
  • FIG. 31 shows GA aggregates are reduced in C9-500 animals treated with metformin compared to C9-500 controls.
  • FIG. 3 J is a schematic showing that chronic activation of the PKR pathway by repeat expansion RNAs favors RAN translation through the integrated stress response and eIF2a phosphorylation.
  • FIGs. 5A-5B show metformin inhibits RAN translation in multiple reading frames in cells that have been transfected with constructs containing CAG, CCTG, or GGGGCC repeat expansion motifs. Protein blots were run on protein lysates from HEK293T cells transfected with various repeat expansion constructs shown in FIG. 5 A.
  • the lane labeled KMQ has a methionine encoding ATG immediately 5' to the CAG repeat expansion and located within the polyGln reading frame.
  • the KKQ vector contains a CAG expansion without an AUG initiation codon, and indicates: Ser-Flag, Ala-HA, Gln-Myc.
  • constructs contain epitope tags that are incorporated into the C-terminal regions of the ATG- initiated poly-Gin and non-ATG initiated RAN proteins (poly-Gin, poly-Leu-Pro-Ala-Cys and poly-Gly-Pro) which are expressed across these repeat expansions.
  • the lane labeled CCTG expresses the following RAN proteins: LP AC -Flag, LPAC-HA, and LPAC-Myc.
  • the lane labeled G4C2 is designed to detect the following RAN proteins: GP-Flag, GR-HA, and GA-Myc.
  • Treatment of the transfected HEK293T cells with metformin shows reduced RAN protein levels of the following RAN proteins of poly-LPAC (poly-Leucine-Proline- Alanine- Cysteine in all three reading frames, poly-Ala, and poly-GP (poly-glycine-proline).
  • poly-LPAC poly-Leucine-Proline- Alanine- Cysteine in all three reading frames
  • poly-Ala poly-Ala
  • poly-GP poly-glycine-proline
  • FIG. 6B shows a schematic diagram showing the study design for two metformin treatment groups, with treatment from 2 to 5 months (Group A) or from 6 to 10 months of age (Group B).
  • FIG. 6C shows
  • FIG. 6D shows soluble GP levels are reduced Group B but not Group A C9-BAC animals treated with metformin compared to controls.
  • FIG. 6E shows DigiGait analyses showing 6 of 8 parameters that differed between untreated C9-BAC and non-transgenic (NT) littermate controls improved in C9-BAC animals treated with metformin.
  • FIG. 6F shows exemplary data of three DigiGait parameters.
  • FIG. 6G shows open-field analyses showing increased center time in C9-BAC animals treated with metformin.
  • FIGs. 6G and 6H show decreased reactive gliosis as measured by GFAP staining (FIG.
  • the disclosure provides a method for administering to a subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin, buformin, phenformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof.
  • a method for administering to the biological sample e.g. , cells or tissue
  • a therapeutically effective amount of a compound described herein e.g. , metformin
  • a biological sample includes, but is not limited to, cells, tissue,
  • the method comprises treating a neurological disease associated with repeat expansions in a subject (e.g. , C90RFf72 amyotrophic lateral sclerosis (ALS) or C90RFf72 frontotemporal dementia; myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2);
  • a neurological disease associated with repeat expansions in a subject e.g. , C90RFf72 amyotrophic lateral sclerosis (ALS) or C90RFf72 frontotemporal dementia; myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2);
  • the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof.
  • the method comprises treating a neurological disease associated with repeat expansions in a biological sample (e.g.
  • cells from a patient with the disease, the method comprising contacting the biological sample with a therapeutically effective amount of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a
  • the method comprises treating a neurological disease associated with repeat expansions in a tissue from a patient with the disease, the method comprising contacting the tissue with a therapeutically effective amount of a compound of Formula (I), (II), (III), (III -A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof.
  • the method comprises treating a neurological disease associated with the accumulation of RAN proteins in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof.
  • Another aspect of the invention relates to methods of treating a neurological disease associated with repeat expansions in a subject or cell, by administering to the subject or contacting the biological sample (e.g. , cells or tissue) with a therapeutically effective amount of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof, whereby the method comprises modulating RAN protein translation.
  • the method comprises modulating the steady state levels of RAN proteins.
  • the method comprises reducing the accumulation of RAN protein in a subject.
  • the method comprises reducing the
  • the method comprises reducing the accumulation of RAN protein in a cell.
  • the modulating comprises negative regulation of RAN protein translation.
  • the modulating comprises inhibition of RAN protein translation.
  • the modulating comprises negative regulation of RAN protein translation and reduced
  • the modulating comprises negative regulation of RAN protein accumulation in a cell or in patient tissue. In certain embodiments, the modulating comprises changes related to translation of RAN proteins. In certain embodiments, the modulating comprises changes related to turnover of RAN proteins.
  • the levels of any RAN protein comprises, in certain embodiments, the steady state levels of one or more RAN proteins.
  • the one or more RAN proteins are selected from the group consisting of poly-Leucine-Proline- Alanine-Cysteine, poly- Glutamine-Alanine-Glycine-Arginine, poly-Glycine-Proline, poly-Glycine-Alanine, poly- Glycine-Arginine, poly-Proline- Alanine, poly-Proline-Arginine, poly- Alanine, poly-Leucine, poly-Serine, poly-Cysteine, poly-Glutamine, poly-Arginine, poly-Glycine, poly-Proline, poly-Isoleucine-Leucine-Phenylalanine-Tyrosine-Serine, Poly-Tryptophan-Asparagine- Glycine-Methionine
  • the method comprises reducing the level of the RAN protein, poly-Leucine-Proline- Alanine-Cysteine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly-Glutamine- Alanine- Glycine-Arginine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly- Glycine-Proline. In certain embodiments, the method comprises reducing the level of the RAN protein poly-Glycine-Alanine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly- Glycine-Arginine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly-Proline- Alanine. In certain
  • the method comprises reducing the level of the RAN protein, poly-Proline- Arginine. In certain embodiments, the method comprises reducing the level of RAN proteins that are poly-Glycine-Leucine, poly-Tryptophan-Alanine, poly-Glutamine-Alanine, poly- Glycine-Proline, and/or poly-Proline-Arginine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly- Alanine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly-Leucine. In certain
  • the method comprises reducing the level of the RAN protein, poly-Serine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly- Cysteine. In certain embodiments, the method comprises reducing the level of the RAN protein, poly-Glutamine. In certain embodiments, the method comprises reducing the level of RAN proteins that are poly-Glutamine, which are associated with spinocerebellar ataxia type 12.
  • the method comprises reducing the level of RAN proteins that are poly-Alanine, poly-Leucine, poly-Serine, and/or poly-Cysteine, which are associated with DM1, spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, 17; spinal bulbar muscular atrophy; dentatorubral-pallidoluysian atrophy (DRPLA), and Huntington's disease.
  • DM1 spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, 17
  • spinal bulbar muscular atrophy spinal bulbar muscular atrophy
  • dentatorubral-pallidoluysian atrophy DRPLA
  • Huntington's disease Huntington's disease.
  • the method comprises reducing the level of RAN proteins that are poly- Glutamine, poly-Alanine, poly-Leucine, poly-Serine, and/or poly-Cysteine, which are associated with Huntington's disease-like 2 syndrome (HDL2); and Fuch' s endothelial corneal dystrophy (FECD).
  • HDL2 Huntington's disease-like 2 syndrome
  • FECD Fuch' s endothelial corneal dystrophy
  • the method comprises reducing the level of RAN proteins that are poly-Arginine, poly-Glycine, poly-Alanine, and/or poly-Proline, which are associated with Fragile X syndrome (FXS); FRAXA; disorders related to 7pl l .2 folate- sensitive fragile site FRA7A; disorders related to folate- sensitive fragile site 2ql l FRA2A; and Fragile XE syndrome (FRAXE).
  • the method comprises reducing the level of RAN proteins that are poly-Alanine, poly-Leucine, poly-Serine, poly- Cysteine, or poly-Leu-Pro-Ala-Cys, which are associated with DM2.
  • FXS Fragile X syndrome
  • FRAXA Fragile XA
  • FRAXA Fragile XA
  • FRA7A disorders related to 7pl l .2 folate- sensitive fragile site
  • FRA7A disorders related to folate- sensitive fragile site 2ql l F
  • the method comprises reducing the level of RAN proteins that are poly-Gln- Ala-Gly-Arg, which are associated with DM2. In certain embodiments, the method comprises reducing the level of RAN proteins that are poly-Gly-Pro, poly-Gly-Arg, poly-Gly-Ala, poly- Pro-Ala, or poly-Pro-Arg, which are associated with sense C90RFf72 ALS and C90RFf72 FTD. In certain embodiments, the method comprises reducing the level of RAN proteins that are poly-Pro-Ala, poly-Pro-Arg, poly-Gly-Pro, poly-Pro-Ala, or poly-Pro-Arg, which are associated with antisense C90RFf72 ALS and antisense C90RFf72 FTD.
  • the method comprises reducing the level of RAN proteins that are Poly- Tryptophan-Asparagine-Glycine-Methionine-Glutamine or poly-Phenylalanine-Histidine- Serine-Isoleucine-Proline, which are associated with spinocerebellar ataxia type 31. In certain embodiments, the method comprises reducing the level of RAN proteins that are poly- Isoleucine-Leucine-Phenylalanine-Tyrosine-Serine, which are associated with spinocerebellar ataxia type 10.
  • Another aspect of the invention relates to methods of reducing the accumulation of repeat associated non-ATG protein (RAN) in a subject, tissue, or cell, the method comprising administering to the subject or cell a therapeutically effective amount of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof, or a
  • the number of poly-amino acid repeats in the RAN protein is at least 35. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 45. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 50. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 70. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 80. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 90. In certain embodiments, the number of poly- amino acid repeats in the RAN protein is at least 100. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 120. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 150. In certain
  • the number of poly-amino acid repeats in the RAN protein is at least 200. In certain embodiments, the number of poly-amino acid repeats in the RAN protein is at least 250.
  • the neurological disease to be treated is associated with repeat expansions (e.g. , repeat expansion mutations that undergo RAN protein translation). In certain embodiments, the neurological disease is associated with the expression of RAN proteins.
  • the repeat expansions comprise GGGGCC expansions and GGCCCC expansions. In certain embodiments, the repeat expansions comprise GGGGCC expansions. In certain embodiments, the repeat expansions comprise GGCCCC expansions. In certain embodiments, the repeat expansions comprise CAG expansions and CTG expansions. In certain embodiments, the repeat expansions comprise CAG expansions. In certain embodiments, the repeat expansions comprise CTG expansions. In certain
  • the repeat expansions comprise CAGG expansions and CCTG expansions. In certain embodiments, the repeat expansions comprise CAGG expansions. In certain embodiments, the repeat expansions comprise CCTG expansions.
  • the neurological disease being treated is a neurodegenerative disorder. In certain embodiments, the neurological disease being treated is a neuromuscular disorder. In certain embodiments, the neurological disease is associated with GGGGCC expansions and/or GGCCCC expansions. In certain embodiments, the neurological disease is associated with GGGGCC expansions and GGCCCC expansions. In certain embodiments, the neurological disease is associated with GGGGCC expansions. In certain embodiments, the neurological disease is associated with GGCCCC expansions. In certain embodiments, the neurological disease associated with GGGGCC expansions and/or GGCCCC expansions is amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the neurological disease associated with GGGGCC expansions and/or GGCCCC expansions is frontotemporal dementia (FTD).
  • the neurological disease associated with GGGGCC expansions and/or GGCCCC expansions is C90RFf72 ALS.
  • the neurological disease is associated with GGGGCC expansions and/or GGCCCC expansions C90RFf72 FTD.
  • the neurological disease is associated with CAG expansions and/or CTG expansions. In certain embodiments, the neurological disease is associated with CAG expansions and CTG expansions. In certain embodiments, the neurological disease is associated with CAG expansions. In certain embodiments, the neurological disease is associated with CTG expansions. In certain embodiments, the neurological disease associated with CAG expansions and/or CTG expansions is spinocerebellar ataxia (SCA). In certain embodiments, the neurological disease is associated with TGGAA expansions. In certain embodiments, the neurological disease associated with TGGAA expansions is spinocerebellar ataxia. In certain embodiments, the neurological disease associated with TGGAA expansions is spinocerebellar ataxia type 31.
  • the neurological disease is associated with 5' GGCCCA expansions of another DNA strand. In certain embodiments, the neurological disease associated with 5' GGCCCA expansions of another DNA strand is spinocerebellar ataxia type 36. In certain embodiments, the neurological disease is associated with ATCCT expansionsln certain embodiments, the neurological disease is associated with 5' ATCCT expansions. In certain embodiments, the neurological disease associated with ATCCT expansions is spinocerebellar ataxia type 10. In certain embodiments, the neurological disease associated with 5' ATCCT expansions is spinocerebellar ataxia type 10. In certain embodiments, the neurological disease is associated with AGGAT expansions of another DNA strand. In certain embodiments, the neurological disease associated with ATCCT expansions of another DNA strand is spinocerebellar ataxia type 36. In certain embodiments, the neurological disease is associated with ATCCT expansionsln certain embodiments, the neurological disease is associated with 5' ATCCT expansions. In certain embodiments, the neurological disease associated with ATCCT expansions
  • the neurological disease is associated with 5' AGGAT expansions of another DNA strand.
  • the neurological disease associated with AGGAT expansions of another DNA strand is spinocerebellar ataxia type 10.
  • the neurological disease associated with 5' AGGAT expansions of another DNA strand is spinocerebellar ataxia type 10.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, or spinocerebellar ataxia type 8.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 1.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 2.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 3.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 8.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, spinocerebellar ataxia type 10, spinocerebellar ataxia type 12, spinocerebellar ataxia type 17, spinocerebellar ataxia type 31, or spinocerebellar ataxia type 36.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 6.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 7.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 10.
  • the spinocerebellar ataxia is spinocerebellar ataxia type 12. In certain embodiments, the spinocerebellar ataxia is spinocerebellar ataxia type 17. In certain embodiments, the spinocerebellar ataxia is spinocerebellar ataxia type 31. In certain embodiments, the spinocerebellar ataxia is spinocerebellar ataxia type 36. In certain embodiments, the neurological disease is myotonic dystrophy type 1 or Fuch's corneal endothelial dystrophy. In certain embodiments, the neurological disease is myotonic dystrophy type 1. In certain embodiments, the neurological disease is Fuch's corneal endothelial dystrophy.
  • the neurological disease is associated with CAGG expansions and/or CCTG expansions. In embodiments, the neurological disease is associated with CAGG expansions and CCTG expansions. In embodiments, the neurological disease is associated with CAGG expansions. In embodiments, the neurological disease is associated with CCTG expansions. In certain embodiments, the neurological disease associated with CAGG expansions and/or CCTG expansions is myotonic dystrophy type 2. In certain embodiments, the neurological disease is associated with RAN protein accumulation.
  • neurological disease is spinal bulbar muscular atrophy or dentatorubral-pallidoluysian atrophy. In certain embodiments, the neurological disease is spinal bulbar muscular atrophy. In certain embodiments, the neurological disease is dentatorubral-pallidoluysian atrophy.
  • the neurological disease is Huntington' s disease.
  • the neurological disease is Fragile X Tremor Ataxia Syndrome (FXTAS).
  • the neurological disease is Huntington's disease-like 2 syndrome (HDL2); Fragile X syndrome (FXS); disorders related to 7pl l .2 folate- sensitive fragile site FRA7A; disorders related to folate-sensitive fragile site 2ql l FRA2A; or Fragile XE syndrome (FRAXE).
  • the present invention provides uses of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof, to reduce the levels of RAN protein in a subject or biological sample (e.g. , cells or tissue).
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g. , metformin
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof to reduce the levels of RAN protein in a subject or biological sample (e.g. , cells or tissue).
  • the present invention provides uses of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof, to reduce the accumulation of RAN protein in a subject or biological sample (e.g. , cells or tissue).
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g.
  • the method comprises modulating (e.g., inhibiting) RAN protein translation.
  • the present invention provides uses of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g., metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof, to treat and/or prevent a neurological disease associated with RAN protein accumulation in a subject in need thereof, and/or in a biological sample (e.g., cells or tissue), whereby the method comprises modulating (e.g., inhibiting) RAN protein translation.
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g., metformin
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof e.g., metformin
  • a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof e.g
  • the present invention provides uses of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g., metformin), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, derivative, or prodrug thereof, to treat and/or prevent a neurological disease associated with repeat expansions (e.g., poly(GP) and/or poly(PR) RAN proteins) in a subject in need thereof, and/or in a biological sample (e.g., cells or tissue),
  • a subject in need thereof is a patient with expansion mutations or micro satellite repeat expansion mutations.
  • the present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g., metformin)and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g., metformin), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a therapeutically effective amount is an amount effective in reducing the level of one or more RAN proteins and treating a neurological disease associated with repeat expansions. In certain embodiments, a therapeutically effective amount is an amount effective in reducing the level of one or more RAN proteins and treating a neurological disease associated with RAN protein accumulation. In certain embodiments, a therapeutically effective amount is an amount effective in reducing the accumulation of RAN proteins.
  • the effective amount is an amount effective in reducing the level of RAN proteins by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%. In certain embodiments, the effective amount is an amount effective in reducing the translation of RAN proteins by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.
  • compositions described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium
  • phosphate dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. , acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. , bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • natural emulsifiers e.g. , acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g. , bentonite (aluminum silicate
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. , carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. , carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • polyoxyethylene sorbitan monolaurate Tween ® 20
  • polyoxyethylene sorbitan Tween ® 60
  • polyoxyethylene sorbitan monooleate Tween ® 80
  • sorbitan monopalmitate Span ® 40
  • sorbitan monostearate Span ® 60
  • sorbitan tristearate Span ® 65
  • glyceryl monooleate sorbitan monooleate
  • sorbitan monooleate (Span ® 80), polyoxyethylene esters (e.g.
  • polyoxyethylene monostearate Myrj ® 45
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
  • polyoxymethylene stearate polyoxymethylene stearate
  • Solutol ® sucrose fatty acid esters
  • polyethylene glycol fatty acid esters e.g. , Cremophor ®
  • polyoxyethylene ethers e.g.
  • polyoxyethylene lauryl ether (Brij ® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g. , cornstarch and starch paste), gelatin, sugars (e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,
  • starch e.g. , cornstarch and starch paste
  • sugars e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium
  • metabisulfite propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g. ,
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyro gen- free water, isotonic s
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • the exemplary liquid dosage forms in certain embodiments are formulated for ease of swallowing, or for administration via feeding tube.
  • disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate
  • solution retarding agents such as paraffin
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • encapsulating agents examples include polymeric substances and waxes.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g. , metformin
  • compositions thereof provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g. , oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intrava
  • Specifically contemplated routes are oral administration, intravenous administration (e.g. , systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g. , systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g. , regional administration via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g. , a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain
  • the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I):
  • each instance of is a single bond or double bond, as valency permits; each instance of R is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
  • each instance of R 4 is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or absent, as valency permits; or, optionally, one instance of R 4 is taken together with R 3 and the intervening atoms to form an optionally substituted 5 to 7- membered heterocyclic ring;
  • each instance of R 6 is independently hydrogen, optionally substituted alkyl, a nitrogen protecting group, or absent, as valency permits;
  • R 7 is hydrogen, optionally substituted alkyl, a nitrogen protecting group or absent, as valency permits.
  • the compound of Formula (I) is of Formula (I- A):
  • each instance of R 2A is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group.
  • the method comprises administering to the subject a therapeutically effective amount of metformin:
  • the method comprises administering to the subject a therapeutically effective amount of a com ound of Formula (II):
  • each instance of is a single bond or double bond, as valency permits;
  • each instance of R 2A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
  • R 3 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group
  • each instance of R 4A is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group
  • each instance of R 6 is independently hydrogen, optionally substituted alkyl, a nitrogen protecting group, or absent, as valency permits;
  • R 7 is hydrogen, optionally substituted alkyl, a nitrogen protecting group, or absent, as valency permits.
  • Formula (II) includes substituent R 2 .
  • R 2 is hydrogen.
  • R 2 is halogen (e.g. , F, CI, Br, or I).
  • R 2 is I.
  • R 2 is -N(R 2A ) 2 , and each instance of R 2A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group (e.g. , - NMe 2 ).
  • R 2 is -NMe 2 .
  • R 2 is -N(R 2A ) 2 , and each instance of R is independently hydrogen or optionally substituted alkyl.
  • R 2 is -(N 15 )(R 2A ) 2 , and each instance of R 2A is independently hydrogen or optionally substituted alkyl.
  • R 2A is as defined herein.
  • Formula (I) includes two instances of substituent R 2A , and Formula (II) includes zero or more instances of substituent R 2A .
  • At least one instance of R 2A is optionally substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 2A is substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 2A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 2A is unsubstituted methyl. In certain embodiments, two instances of R 2A are unsubstituted methyl. In certain embodiments, at least one instance of R 2A is unsubstituted methyl or unsubstituted ethyl. In certain embodiments, at least one instance of R 2A is optionally substituted methyl.
  • At least one instance of R 2A is - CH 2 (D). In certain embodiments, at least one instance of R 2A is unsubstituted methyl. In certain embodiments, at least one instance of R 2A is -CD3. In certain embodiments, both instances of R 2A are -CD3. In certain embodiments, at least one instance of R 2A is
  • R 2A unsubstituted ethyl.
  • at least one instance of R 2A is optionally substituted ethyl.
  • at least one instance of R 2A is substituted ethyl.
  • At least one instance of R 2A is of the formula: ⁇ .
  • at least one instance of R 2A is optionally substituted n-propyl.
  • at least one instance of R 2A is unsubstituted n-propyl.
  • at least one instance of R 2A is a nitrogen protecting group (e.g. , benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • Formulae (I) and (II) include substituent R 3 .
  • R 3 is hydrogen.
  • at least one instance of R 3 is optionally substituted alkyl (e.g. , substituted or unsubstituted Ci- ⁇ alkyl).
  • R 3 is optionally substituted C 1-6 alkyl.
  • R 3 is unsubstituted C 1-6 alkyl.
  • R 3 is unsubstituted methyl or unsubstituted ethyl.
  • R 3 is unsubstituted methyl.
  • R 3 is optionally substituted methyl.
  • R 3 is optionally substituted ethyl. In certain embodiments, R 3 is unsubstituted ethyl. In certain embodiments, R 3 is a nitrogen protecting group (e.g. , benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • benzyl Bn
  • t-butyl carbonate BOC or Boc
  • Boc benzyl carbamate
  • Fmoc 9-fluorenylmethyl carbonate
  • Ts p-toluenesulfonamide
  • Formula (II) includes substituent R 4 .
  • R 4 is hydrogen.
  • R 4' is -N(R 4 ) 2 , and each instance of R 4 is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or absent, as valency permits.
  • R 4 is ⁇ , and each instance of R 4 is independently hydrogen or
  • R is , In certain embodiments,
  • R 4 is as defined herein.
  • Formulae (I) and (II) each include one or more instances of substituent R 4 . In certain embodiments, one instance of R 4 is absent. In certain embodiments, Formulae (I) and (II) each include two instances of substituent R 4 . In certain embodiments, Formulae (I) and (II) each include three instances of substituent R 4 .
  • each instance of R 4 is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or absent, as valency permits; or, optionally, one instance of R 4 is taken together with R 3 and the intervening atoms to form an optionally substituted 5 to 7-membered heterocyclic ring; or optionally, when one instance of R 4 is taken together with R 3 and the intervening atoms to form an optionally substituted 5 to 7-membered heterocyclic ring, is a double bond, as valency permits.
  • at least one instance of R 4 is hydrogen.
  • both instances of R 4 are hydrogen.
  • at least one instance of R 4 is deuterium.
  • both instances of R 4 are deuterium.
  • at least one instance of R 4 is optionally substituted alkyl (e.g. , substituted or unsubstituted C 1-6 alkyl).
  • at least one instance of R 4 is optionally substituted Ci- ⁇ alkyl.
  • at least one instance of R 4 is unsubstituted C 1-6 alkyl.
  • at least one instance of R 4 is unsubstituted methyl or unsubstituted ethyl.
  • at least one instance of R 4 is optionally substituted methyl.
  • at least one instance of R 4 is -CH 2 (D).
  • At least one instance of R 4 is unsubstituted methyl. In certain embodiments, two instances of R 4 are unsubstituted methyl. In certain embodiments, at least one instance of R 4 is -CD 3 . In certain embodiments, both instances of R 4 are -CD 3 . In certain embodiments, at least one instance of R 4 is unsubstituted ethyl. In certain embodiments, at least one instance of R 4 is a nitrogen protecting group (e.g.
  • R 4 is taken together with R 3 and the intervening atoms to form an optionally substituted 6- membered heterocyclic ring.
  • the compound of Formula (I) is of the
  • Formulae (I) and (II) each include one or more instances of substituent R 6 . In certain embodiments, one instance of R 6 is absent. In certain embodiments, Formulae (I) and (II) each include two instances of substituent R 6 . In certain embodiments, Formulae (I) and (II) each include three instances of substituent R 6 . In certain embodiments, each instance of R 6 is independently hydrogen, optionally substituted alkyl, a nitrogen protecting group, or absent, as valency permits. In certain embodiments, at least one instance of R 6 is hydrogen. In certain embodiments, two instances of R 6 are hydrogen. In certain embodiments, at least one instance of R 6 is deuterium. In certain embodiments, two instances of R 6 are deuterium.
  • At least one instance of R 6 is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 6 is unsubstituted methyl or unsubstituted ethyl. In certain embodiments, at least one instance of R 6 is optionally substituted methyl. In certain embodiments, at least one instance of R 6 is - CH 2 (D). In certain embodiments, at least one instance of R 6 is unsubstituted methyl. In certain embodiments, two instances of R 6 are unsubstituted methyl. In certain embodiments, at least one instance of R 6 is -(C-l 1)H 3 or -(C- 13)H 3 .
  • At least one instance of R 6 is -(C-l 1)H 3 . In certain embodiments, at least one instance of R 6 is -(C- 13)H 3 . In certain embodiments, at least one instance of R 6 is -CD 3 . In certain embodiments, both instances of R 6 are -CD 3 . In certain embodiments, at least one instance of R 6 is unsubstituted ethyl. In certain embodiments, at least one instance of R 6 is a nitrogen protecting group (e.g.
  • benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • Formulae (I) and (II) each include substituent R 7 .
  • R 7 is independently hydrogen, optionally substituted alkyl, a nitrogen protecting group, or absent, as valency permits. In certain embodiments, R 7 is absent. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is deuterium. In certain embodiments, R 7 is optionally substituted alkyl (e.g. , substituted or unsubstituted C 1-6 alkyl). In certain embodiments, R 7 is optionally substituted Ci- ⁇ alkyl. In certain embodiments, R 7 is unsubstituted C 1-6 alkyl. In certain embodiments, R 7 is unsubstituted methyl or unsubstituted ethyl. In certain embodiments, R 7 is independently hydrogen, optionally substituted alkyl, a nitrogen protecting group, or absent, as valency permits. In certain embodiments, R 7 is absent. In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is deuterium.
  • R 7 is optionally substituted methyl. In certain embodiments, R 7 is -CH 2 (D). In certain embodiments, R 7 is unsubstituted methyl. In certain embodiments, R 7 is -CD 3 . In certain embodiments, R 7 is unsubstituted ethyl. In certain embodiments, R 7 is a nitrogen protecting group (e.g. , benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p- toluenesulfonamide (Ts)).
  • a nitrogen protecting group e.g. , benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoro
  • x is 0 or 1 ;
  • the compound of Formula (I) is of the formula:
  • the compound of Formula (I) is of the formula:
  • the compound of Formula (I) is of the formula: . In certain embodiments, the compound of Formula (I) is of the formula:
  • the compound of Formula (I) is of the formula: . in certain embodiments, the compound of Formula (I) is of the formula:
  • the compound of Formula (II) is of the formula:
  • x is 0 or 1 ;
  • the compound of Formula (II) is of the formula:
  • the compound of Formula (II) is of the
  • the compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt thereof.
  • Formulae (I) and (II) include zero or more instances of substituent R 10 .
  • x is 0.
  • x is 1.
  • at least one instance of R 10 is halogen (e.g. , F, CI, Br, or I).
  • at least one instance of R 10 is I.
  • at least one instance of R 10 is optionally substituted alkyl (e.g. , substituted or unsubstituted C 1-6 alkyl).
  • at least one instance of R 10 is optionally substituted C 1-6 alkyl.
  • At least one instance of R 10 is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 10 is unsubstituted methyl or unsubstituted ethyl. In certain embodiments, at least one instance of R 10 is unsubstituted methyl. In certain embodiments, at least one instance of R 10 is optionally substituted methyl. In certain embodiments, at least one instance of R 10 is optionally substituted ethyl. In certain embodiments, at least one instance of R 10 is unsubstituted ethyl. In certain embodiments, at least one instance of R 10 is -NH 2 .
  • At least one instance of R 10 is -N(optionally substituted alkyl) 2 (e.g. , - N(substituted or unsubstituted C 1-6 alkyl) 2 ). In certain embodiments, at least one instance of R 10 is -NH(optionally substituted alkyl) 2 (e.g. , -NH(substituted or unsubstituted C 1-6 alkyl).
  • R 5 is optionally substituted acyl, unsubstituted alkyl, unsubstituted carbocyclyl, or optionally substituted aryl;
  • each instance of R 5A is independently -0(optionally substituted alkyl), -OH, -NH 2 , - NH(optionally substituted alkyl), or -N(optionally substituted alkyl) 2 ;
  • n 0, 1, 2, 3, or 4.
  • n there are zero or more instances of R 5A .
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.
  • each instance of R 5A is independently -0(optionally substituted alkyl), -OH, -NH 2 , or -N(optionally substituted alkyl) 2 . In certain embodiments, at least one instance of R 5A is -0(optionally substituted alkyl) (e.g. , -0(optionally substituted C 1-6 alkyl)). In certain embodiments, at least one instance of R 5A is -OMe.
  • At least one instance of R 5A is -OH. In certain embodiments, at least one instance of R 5A is -NH 2 . In certain embodiments, at least one instance of R 5A is -N(optionally substituted alkyl) 2 (e.g. , -N (optionally substituted C 1-6 alkyl) 2 ). In certain embodiments, at least one instance of R 5A is -NMe 2 . In certain embodiments,
  • At least one instance of R 5A is -NH(optionally substituted alkyl).
  • a compound of Formulae (I) or (II) is of the formula:
  • At least one hydrogen atom is deuterium.
  • at least one carbon atom is C-l 1.
  • at least one carbon atom is C-l 3.
  • at least one nitrogen atom is N- 15.
  • a compound of Formulae (I) or (II) is of the formula:
  • the compound of Formula (I) is of the formula: (phenformin),
  • the compound of Formula (I) is of the formula:
  • the compound of Formula (I) is of the formula:
  • At least one instance of R 4A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R 4A is unsubstituted methyl or unsubstituted ethyl. In certain embodiments, at least one instance of R 4A is optionally substituted methyl. In certain embodiments, at least one instance of R 4A is unsubstituted methyl. In certain embodiments, at least one instance of R 4A is unsubstituted ethyl. In certain embodiments, at least one instance of R 4A is a nitrogen protecting group (e.g.
  • R 4A is -CN.
  • benzyl (Bn), t- butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • R 9 is -CN.
  • R 9 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).
  • nitrogen protecting group e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)
  • a compound described herein is formulated as a tablet with hydrobromic acid.
  • a compound described herein is formulated as a tablet with phosphoric acid.
  • a compound described herein is formulated as a tablet with sulfuric acid.
  • a compound described herein is formulated as a tablet with perchloric acid.
  • a compound described herein is formulated as a tablet with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid.
  • a compound described herein is formulated as a tablet using other methods known in the art such as ion exchange.
  • a a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin)and compositions thereof, in certain embodiments, is administered via an enteral (e.g. , oral) route.
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin) is administered in doses of 500 mg metformin twice a day or doses of 850 mg metformin once a day.
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g.
  • metformin is administered in doses of at least 825 mg metformin three times a day.
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g. , metformin is administered in doses of 825 mg metformin three times a day.
  • (III) , (III-A), or (III-B) e.g. , metformin
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g. , metformin
  • doses of 1000 mg once a day are given with meals.
  • the method comprises administering to the subject a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin)over a period between 10 days to 30 days.
  • the duration between the first dose and last dose of the multiple doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin) is 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days.
  • the duration between the first dose and last dose of the multiple doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) is at least the following number of days: 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days.
  • the duration between the first dose and last dose of the multiple doses of metformin is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, multiple months, at least one year, multiple years, at least one decade, or multiple decades.
  • the doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) are administered indefinitely.
  • the doses of metformin are administered over a lifetime of the subject.
  • a dose described herein is at least 500 mg, 600 mg, 650 mg, 750 mg, 700 mg, 800 mg, 825 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 5000 mg, 8000 mg, 9000 mg, or 10,000 mg of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin).
  • the duration between the first dose and last dose of the multiple doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g.
  • metformin is based on the duration required to prevent the accumulation of RAN proteins in a subject.
  • the duration between the first dose and last dose of the multiple doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin) is based on the duration required to reduce the level of RAN proteins in a subject.
  • the multiple doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) e.g. , metformin
  • the prophylactic treatment is long-term, in certain embodiments.
  • the multiple doses of a compound of Formula (I), (II), (III), (III-A), or (III-B) are administered as long-term therapeutic treatment to reduce the level of RAN proteins in a subject.
  • the subject in certain embodiments, has a microsatellite expansion mutation including but not limited to mutations that cause: C9orf72 ALS or C9orf72 FTD, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2); spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, 31, and 36; spinal bulbar muscular atrophy; dentatorubral-pallidoluysian atrophy (DRPLA); Huntington' s disease (HD); Fragile X Tremor Ataxia Syndrome (FXTAS); Huntington's disease-like 2 syndrome (HDL2);
  • Fragile X syndrome FXS
  • disorders related to 7pl l .2 folate-sensitive fragile site FRA7A disorders related to folate-sensitive fragile site 2ql l FRA2A
  • Fragile XE syndrome FXS
  • FXS Fragile X syndrome
  • disorders related to 7pl l .2 folate-sensitive fragile site FRA7A disorders related to folate-sensitive fragile site 2ql l FRA2A
  • Fragile XE syndrome FXS
  • Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin)or compositions thereof, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g. , therapeutically and/or prophylactically active agents).
  • additional pharmaceutical agents e.g. , therapeutically and/or prophylactically active agents.
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g. , activity (e.g.
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • compositions thereof can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g. , combination therapies.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds (e.g. , compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,
  • the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g. , neurological disease).
  • a disease e.g. , neurological disease
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain-relieving agents, and a combination thereof.
  • additional pharmaceutical agents include, but are not limited to, cardiovascular agents, anti-diabetic agents, and agents for treating and/or preventing a neurological disease.
  • the additional pharmaceutical agents include, but are not limited to, anti-inflammatory agents or compounds (e.g. , turmeric).
  • kits e.g. , pharmaceutical packs
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g. , a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
  • the pharmaceutical composition or compound described herein in some embodiments, are combined to form one unit dosage form.
  • kits described herein further includes instructions for using a compound of Formula (I), (II), (III), (III-A), or (III-B) (e.g. , metformin), or
  • kits and instructions provide for treating a disease (e.g. , a neurological disease) in a subject in need thereof.
  • the kits and instructions provide for preventing a disease (e.g. , a neurological disease) in a subject in need thereof.
  • the kits and instructions provide for reducing the level of one or more RAN proteins in a subject, biological sample, tissue, or cell.
  • kits and instructions provide for reducing the accumulation of RAN proteins in a subject, biological sample, tissue, or cell. In certain embodiments, the kits and instructions provide for modulating (e.g. , reducing or inhibiting) RAN protein translation in a subject, biological sample, tissue, or cell.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • Metformin was evaluated for its effect on RAN protein translation in HEK293T cells that have been transfected with constructs containing CAG, CCTG or GGGGCC repeat expansion motifs. Transfected HEK293T cells were treated with metformin. Protein blots were run on protein lysates from HEK293T cells transfected with various repeat expansion constructs shown in FIG. 1A. In FIG. IB, the lanes labeled KMQ, show: RAN poly-Ser-Flag, RAN poly-Ala-HA, ATG initiated polyGln-Myc. In FIG.
  • the lanes labeled KMQ has a methionine encoding ATG immediately 5' to the CAG repeat expansion and located within the polyGln reading frame.
  • the lanes labeled KKQ indicate the KKQ vector contains a CAG expansion without an AUG initiation codon, and indicates: RAN polySer-Flag, RAN poly Ala- HA, RAN polyGln-Myc.
  • These constructs contain epitope tags that are incorporated into the C-terminal regions of the ATG-initiated poly-Gin and non-ATG initiated RAN proteins (poly-Gin, poly-Leu-Pro-Ala-Cys and poly-Gly-Pro) which are expressed across these repeat expansions.
  • the lane labeled CCTG expresses the following RAN proteins: RAN polyLPAC-Flag, RAN polyLPAC-HA, RAN polyLPAC-Myc.
  • the lane labeled G4C2 is designed to detect the following RAN proteins: RAN polyGP-Flag, RAN polyGR-HA, RAN polyGA-Myc.
  • the protein blots in FIG. IB show reduced RAN protein levels of the following RAN proteins of poly-LPAC (poly-Leucine-Proline- Alanine-Cysteine) in all three reading frames, poly-Ala, and poly-GP (poly glycine-proline).
  • FIG. IB shows that metformin inhibits RAN protein accumulation in cells transfected with exemplary repeat expansion constructs.
  • Metformin was evaluted for its effect on the steady state levels of glycine-proline (GP) RAN protein detected in vivo in proteins extracted from peripheral blood of a C90RF72 expansion-positive study subject before and after treatment with metformin C90RF72. These levels were measured in a human study subject before and after the subject was administered metformin (500 mg or 1000 mg per day Metformin Hydrochloride Extended Release Tablets) at different doses as prescribed by the subject's physician. Dose dependent reduction of glycine -proline (GP) RAN protein levels was observed in blood samples taken from a single human subject with a C90RF72 repeat expansion compared to pretreatment levels.
  • metformin 500 mg or 1000 mg per day Metformin Hydrochloride Extended Release Tablets
  • This Example describes activation of the PKR pathway by structured RAN -positive repeat expansion RNAs.
  • the activation leads to increased phospho- eIF2a (p-eIF2a) and increased RAN protein levels. It was observed that inhibition of PKR decreased RAN protein levels in cell culture and a BAC transgenic mouse model of C9orf72 ALS/FTD (C9-BAC). It was also observed that metformin (and certain metformin
  • derivatives for example buformin and phenformin
  • inhibits phospho-PKR activation decreases RAN protein levels and improves phenotypes in C9-BAC mice.
  • Gait analysis Digital video images of the underside of the mouse were collected with a high-speed video camera from below the transparent belt of a motorized treadmill (DigiGaitTM Imaging system, Mouse Specific). Each mouse was allowed to explore the treadmill compartment with the motor speed set to 14 cm/s for lmin then the motor speed was increased to 24 cm/s for video recording. Only video recordings in which the mouse walked straight ahead with a constant relative position with respect to the camera were used for analysis. Data from each paw was analyzed with DigiGait automated gait analysis software (Mouse Specifics).
  • Open field analysis Open field analysis was performed by testing mouse behavior during a 30 min session in a completely dark open chamber (17"xl7") (Med Associates). Approximately two hours before the start of analysis, mice were placed in the testing room to allow for acclimation to the room. Mice were then placed in the center of the darkened activity-monitoring chamber. The trace path and center time was recorded and analyzed with Activity Monitor (MED associates, Inc.) software.
  • Activity Monitor MED associates, Inc.
  • HEK293T cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and incubated at 37°C in a humid atmosphere containing 5% C0 2 .
  • DNA transfections were performed using Lipofectamine 2000 Reagent (Invitrogen) according to the manufacturer's instructions.
  • AAV vectors expressing the PKR under the control of the cytomegalovirus enhance/chicken beta actin (CBA) promoter, a woodchuck hepatitis virus post- transcriptional-regulatory element (WPRE), and the bovine growth hormone polyA were generated by Polyethylenimine Linear (PEI, Polysciences) transfection into HEK293T cells. Cells were co-transfected with AAV helper plasmids pDP8.ape to produce recombinant adeno-associated viral (rAAV) vector rAAV2/8.
  • CBA cytomegalovirus enhance/chicken beta actin
  • WPRE woodchuck hepatitis virus post- transcriptional-regulatory element
  • polyA bovine growth hormone polyA
  • Neonatal pups were injected within 0-12 hours after birth. The naive pups were covered in aluminum foil and completely surrounded in ice for 3-4 minutes, resulting in the body temperature being lowered to ⁇ 10 °C. The pups were considered completely cryoanesthetized when all movement stops and the skin color changes from pink to purple. 2 ⁇ of virus (1013 viral genomes/ml) was slowly injected into the ventricle using 10 ⁇ syringes (30 degree beveled). After injection pups were allowed to completely recover on a warming blanket and then returned to the home cage.
  • the cells were incubated for 1 hour at RT in blocking solution containing the rabbit anti-Myc (Abeam), mouse anti-HA (Covanee), mouse anti-Flag (Sigma), rabbit a-GR and rabbit a-GR-CT primary antibodies at a dilution of 1:400.
  • the slides were washed three times in PBS and incubated for 1 hour at RT in blocking solution containing Goat anti-rabbit conjugated to Cy3 (Jackson ImmunoResearch, PA) and goat anti- mouse conjugated to Alexa Fluor 488 (Invitrogen) secondary antibodies at a dilution of 1:200.
  • the slides were washed three times in PBS and mounted with mounting medium containing DAPI (Invitrogen).
  • the membrane was blocked in 5% dry milk in PBS containing 0.05% Tween-20 (PBS-T) and probed with the anti-Flag (1:2000), anti-Myc (1: 1000), anti-HA (1: 1000), or rabbit polyclonal antibodies (1: 1000) in blocking solution. After the membrane was incubated with anti-rabbit or anti-mouse HRP-conjugated secondary antibody (Amersham), bands were visualized by the ECL plus Western Blotting Detection System (Amersham).
  • Sequential extraction of patient frontal cortex autopsy tissue was performed as follows: tissue was homogenized in PBS containing 1% Triton-XlOO, 15 mM MgCl 2 , 0.2 mg/ml DNase I and protease inhibitor cocktail and centrifuged at 16,000 x g for 15 min at 4 °C. The supernatant was collected. The pellet was resuspended in 2 % SDS and incubated at room temperature for 1 hour, then centrifuged at 16,000 x g for 15 min at 4 °C.
  • the supernatant was collected and the 2 % SDS insoluble pellet was resuspended in 8 % SDS, 62.5 mM Tris-HCl pH 6.8, 10 % glycerol, and 20 % 2-mercaptoethanol for protein blotting.
  • Metformin decreases RAN translation and mitigates repeat-induced PKR activation
  • metformin decreases RAN protein levels in cells expressing CAG, CCUG or G 4 C 2 expansion RNAs (FIG. 3A).
  • RAN protein inhibition by metformin is similar to the inhibition with PKR-K296R, indicating that metformin mitigates PKR activation induced by repeat expansion RNAs.
  • Transient transfections of expansion constructs treated with or without metformin were performed. Protein blots indicate that metformin decreases PKR phosphorylation at T446 and T451, sites which have been observed to be required for PKR activation (FIG. 3B).
  • metformin and the related drugs phenformin and buformin mediate similar dose-dependent inhibition of G 4 C 2 repeat-expansion induced p-PKR levels and RAN polyGP levels (FIG. 4).
  • metformin reduced the levels of several types of RAN proteins in mammalian cells and PKR was identified as a metformin target that inhibits PKR activation and eIF2a phosphorylation. [00182] Metformin ameliorates neuropathological and behavioral phenotypes in the C9-500 mouse model.
  • C9orf72 mice, C9-500 BAC and NT mice were treated for 3 months with or without metformin (5 mg/ml) in the drinking water.
  • metformin 5 mg/ml
  • treatment began at 2 months of age, before the onset of overt behavioral or pathological phenotypes.
  • FIG. 3C A schematic depicting treatment regimens is shown in FIG. 3C. DigiGait analyses of Group A mice at 5 months identified eight DigiGait parameters that differed between untreated C9 and NT cohorts. In C9 metformin treated mice, six of these parameters improved compared to the C9 water treatment group (FIGs. 3E- 3G). Similarly, Group A metformin-treated C9 mice showed increased center time by open field testing, compared to untreated C9 mice. These data indicate that this anxiety-like behavior is improved by metformin treatment (FIG. 3G
  • C9 metformin treated animals showed decreased numbers of GA aggregates in the retrosplenial cortex compared to C9 controls in cohorts that began treatment at presymptomatic (8 wks, Group A) or symptomatic ages (6 mos, Group B) (FIG. 3D). Decreases in soluble GP levels were observed in C9 metformin treated animals compared to C9 controls in the older Group B but not the younger Group A treatment cohorts (FIGs. 3H-3I).
  • GFAP glial fibrillary acidic protein
  • data indicate that metformin reduces RAN protein levels in vitro and in vivo, and metformin treatment improves behavior and decreases neuroinflammation in C9 BAC transgenic mice.
  • data described in this example are consistent with a model in which repeat expansion RNAs lead to chronic activation of the PKR pathway, a condition which results in increased levels of p-eIF2a, decreases in global protein synthesis and the upregulation of RAN translation (FIG. 3J).
  • Metformin was evaluated for its effect on RAN protein translation in HEK293T cells that have been transfected with constructs containing CAG, CCTG or GGGGCC repeat expansion motifs.
  • Transfected HEK293T cells were treated with metformin.
  • Protein blots were run on protein lysates from HEK293T cells transfected with various repeat expansion constructs shown in FIG. 5A.
  • FIG. 5B the lanes labeled KMQ, show: RAN poly-Ser-Flag, RAN poly-Ala-HA, ATG initiated polyGln-Myc.
  • FIG. 5B the lanes labeled KMQ, show: RAN poly-Ser-Flag, RAN poly-Ala-HA, ATG initiated polyGln-Myc.
  • the lane labeled CCTG expresses the following RAN proteins: RAN polyLPAC-Flag, RAN polyLPAC-HA, RAN polyLPAC-Myc.
  • the lane labeled G4C2 is designed to detect the following RAN proteins: RAN polyGP-Flag, RAN polyGR-HA, RAN polyGA-Myc.
  • the protein blots in FIG. 13B show reduced RAN protein levels of the following RAN proteins of poly-LPAC (poly-Leucine-Proline- Alanine-Cysteine) in all three reading frames, poly-Ala, and poly-GP (poly glycine-proline).
  • FIG. 5B shows that metformin inhibits RAN protein accumulation in cells transfected with exemplary repeat expansion constructs.
  • FIG. 5B shows that metformin decreases poly Ala, poly LP AC and polyGP RAN protein levels, but not polyGln levels in cells expressing CAG, CCUG or G 4 C 2 expansion RNAs.
  • exemplary compound metformin inhibits PKR activation induced by repeat expansion RNAs
  • repeat expansion transcripts were expressed with or without metformin.
  • Protein blots show that PKR metformin decreases PKR phosphorylation at the T446 and T451 sites, which are required for PKR activation (Fig. 6A).
  • exemplary metformin and the exemplary related drugs phenformin and buformin show similar dose- dependent inhibition of G 4 C 2 repeat-expansion induced p-PKR levels and RAN polyGP levels (see FIG. 4).
  • exemplary compound metformin reduces the levels of several types of RAN proteins in mammalian cells and a novel function of metformin as a modulator of PKR phosphorylation has been identified.
  • Metformin was evaluated for its effect on the steady state levels of glycine-proline (GP) RAN protein detected in vivo in proteins extracted from peripheral blood of a C90RF72 expansion-positive study subject before and after treatment with metformin C90RF72. These levels were measured in a human study subject before and after the subject was administered metformin (500 mg or 1000 mg per day Metformin Hydrochloride Extended Release Tablets) at different doses as prescribed by the subject's physician. Dose dependent reduction of glycine -proline (GP) RAN protein levels was observed in blood samples taken from a single human subject with a C90RF72 repeat expansion compared to pretreatment levels.
  • metformin 500 mg or 1000 mg per day Metformin Hydrochloride Extended Release Tablets
  • Example 5 Evaluation of Exemplary Compound Metformin ameliorating neuropathological and behavioral phenotypes in the C9-BAC mouse model.
  • Alzheimer's amyloid peptides via up-regulating BACE1 transcription Proc Natl Acad Sci U SA 106, 3907-3912, doi: 10.1073/pnas.0807991106 (2009); Foretz, M., Guigas, B., Bertrand, L., Pollak, M. & Viollet, B. Metformin: from mechanisms of action to therapies. Cell Metab 20, 953-966, doi: 10.1016/j.cmet.2014.09.018 (2014); Memmott, R. M. et al. Metformin prevents tobacco carcinogen— induced lung tumorigenesis. Cancer Prev Res (Phila) 3, 1066- 1076, doi: 10.1158/1940-6207.CAPR- 10-0055 (2010)).
  • Group A animals three months of treatment began at 2 months of age, before the onset of overt behavioral or pathological phenotypes.
  • Group B smaller cohorts of animals were treated for four months beginning at 6 months, an age at which behavioral phenotypes are evident 12 .
  • metformin did not change C9orf72 mRNA levels.
  • TAR RNA-binding protein is an inhibitor of the interferon-induced protein kinase PKR. Proc Natl Acad Sci U S A 91, 4713-4717 (1994).
  • GlucophageR Antidiabetic drug metformin
  • Amyotrophic Lateral Sclerosis A Population-Based Study. JAMA Neurol 72, 905-911, doi: 10.1001/jamaneurol.2015.0910 (2015).
  • Neuron 78 440-455.

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