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`April 9, 2015
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`Re:
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`UNITED STATES DEPARTMENT OF COMMERCE
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`Electronic Acknowledgement Receipt
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`EFSID:
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`1502966
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`60888921
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`International Application Number:
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`Confirmation Number:
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`1657
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`Title of Invention:
`
`Nrf2 SCREENING ASSAYS AND RELATED METHODS AND
`COMPOSITIONS
`
`First Named Inventor/Applicant Name:
`
`....
`
`Customer Number:
`
`65779
`
`Filer:
`
`Konstantin LinniklKathleen Camire
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`Filer Authorized By:
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`Konstantin Linnik
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`Attorney Docket Number:
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`08201.6042-00000
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`PROVISIONAL APPLICATION COVER SHEET
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`I Docket Number 08201.6042-00000
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`COUNTRy)
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`TITLE OF INVENTION (500 characters max)
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`Nrf2 SCREENING ASSAYS AND RELATED METHODS AND COMPOSITIONS
`
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`
`BIOGEN IDEC I FINNEGAN HENDERSON, LLP
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`Customer Number 65,779
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`authorized to charge any
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`The invention was made by an agency of the United States Government or under a contract with an
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`IX! No.
`o Yes, the name of the U.S. Government agency and the Government contract number are:
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`Respectfully sUbmitti~n
`rl· I
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`alf of the pate!)t practitioners associated with Customer Number 65,779.
`"
`SIGNATURE
`------~~~--------~------
`
`Date February 8, 2007
`
`TYPED OR PRINTED NAME Konstantin M. Linnik
`
`REGISTRATION NO. 56,309
`
`o Additional inventors are being named on separately numbered sheets attached hereto.
`
`PROVISIONAL APPLICATION FILING ONLY
`
`Page 7 of 49
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`
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`Attorney Docket No. 08201.6042-00000
`
`Nrf2 SCREENING ASSAYS
`AND RELATED METHODS AND COMPOSITIONS
`
`[0001]
`
`The invention relates to the field of cell and molecular biology and
`
`to the development and use of therapeutic compounds, more particularly,
`
`compounds for treating neurological diseases, including demyelinating
`
`neurological diseases, such as, e.g., multiple sclerosis.
`
`[0002] Multiple sclerosis (MS) is an autoimmune disease with the
`
`autoimmune activity directed against central nervous system (eNS) antigens.
`
`The disease is characterized by inflammation in parts of the eNS, leading to the
`
`loss of the myelin sheathing around neuronal axons (demyelination), loss of
`
`axons, and the eventual death of neurons, oligodenrocytes and glial cells.
`
`[0003] An estimated 2,500,000 people in the world suffer from MS. It is
`
`one of the most common diseases of the eNS in young adults. MS is a chronic,
`
`progressing, disabling disease, which generally strikes its victims some time after
`
`adolescence, with diagnosis generally made between 20 and 40 years of age,
`
`although onset may occur earlier. The disease is not directly hereditary,
`
`although genetic susceptibility plays a part in its development.
`
`Relapsing-remitting MS presents in the form of recurrent attacks of focal or
`
`multifocal neurologic dysfunction. Attacks may occur, remit, and recur,
`
`seemingly randomly over many years. Remission is often incomplete and as one
`
`attack follows another, a stepwise downward progression ensues with increasing
`
`permanent neurological deficit.
`
`[0004] Although various immunotherapeutic drugs can provide relief in
`
`patients with MS, none is capable of reversing disease progression, and some
`
`can cause serious adverse effects. Most current therapies for MSare aimed at
`
`the reduction of inflammation and suppression or modulation of the immune
`
`system. As of 2006, the available treatments for MS reduce inflammation and
`
`the number of new episodes but not all have an effect on disease progression. A
`
`number of clinical trials have shown that the suppression of inflammation in
`
`chronic MS rarely significantly limits the accumulation of disability through
`
`1
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`Page 8 of 49
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`Attorney Docket No. 08201.6042-00000
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`sust~ined disease progression, suggesting that neuronal damage and
`inflammation are independent pathologies. Promoting CNS remyelination as a
`repair mechanism and otherwise preventing axonal loss and neuronal death are
`some of the important goals for the treatment of MS. For a comprehensive
`review of MS and its current therapies, see, e.g., McAlpine's Multiple Sclerosis,
`by Alastair Compston et aI., 4th edition, Churchill Livingstone Elsevier, 2006.
`[0005] "Phase 2 enzymes" serve as a protection mechanism in
`mammalian cells against oxygenlnitrogen species (ROS/RNS), electrophiles and
`xenobiotics. These enzymes are not normally expressed at their maximal levels
`and, their expression can be induced by a variety of natural and synthetic agents.
`Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor responsible for
`the induction of a variety of important antioxidant and detoxification enzymes that
`coordinate a protective cellular response to metabolic and toxic stress.
`[0006] ROS/RNS are most damaging in the brain and neuronal tissue,
`where they attack post-mitotic (i.e., non-dividing) cells such as glial cells,
`oligodendocytes, and neurons, which are particularly sensitive to free radicals.
`This process leads to neuronal damage. Oxidative stress has been implicated in
`the pathogenesis of a variety of neurodegenerative diseases, including ALS,
`Alzheimer's disease (AD), and Parkinson's disease (PD). For review, see, e.g.,
`van Muiswinkel et aI., Curro Drug Targets CNS--Neurol. Disord., 2005, 4:267-281.
`An anti-oxidative enzyme under control of Nrf2, NQ01 (NAD(P)H
`dehydrogenase, quinone 1), was recently reported to be substantially
`upregulated in the brain tissues of AD and PD subjects (Muiswinkel et aI.,
`Neurobiol.Aging, 2004, 25: 1253). Similarly, increased expression of NQ01 was
`reported in the ALS subjects' spinal cord (Muiswinkel et al., Curro Drug
`Targets--CNS. Neurol. Disord., 2005, 4:267-281) and in active and chronic
`lesions in the brains of patients suffering from MS (van Horssen et aI., Free
`Radical BioI. & Med., 2006, 41 311-311). TtJese observations indicate that the
`Nrf2 pathway may be activated in neurodegenerative and neuroinflammatory
`diseases as an endogenous protective mechanism. Indeed, most recently; it has
`
`2
`
`Page 9 of 49
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`Attorney Docket No. 08201.6042-00000
`
`been reported that induced activation of Nrf2-dependent genes by certain
`
`cyclopenanone-based compounds (NEPP) counters the toxic effects of metabolic
`
`inhibition and ROS/RNS production in the brain and protects neurons from death
`
`in vitro and in vivo (see Satoh et aI., PNAS, 2006, 103(3):768-773).
`
`[0007] Additionally, many publications have reported neuroprotective
`
`effects of compounds in natural plant-derived compounds ("phytochemicals"),
`
`including a-tocopherol (vitamin E), Iycopene (tomatoes), resveratrol (red grapes),
`
`sulforaphane (broccoli), EGCG (green tea), etc. For review, see Mattson and
`
`Cheng, Trends in Neurosci., 2006, 29(11):632-639. Originally, the action of
`
`these compounds was attributed to their anti-oxidant properties. However, while
`
`most anti-oxidants are effective only at high concentrations, at least some of
`
`these compounds appear to exert neuroprotective effects at much lower doses.
`
`Emerging evidence suggests that these compounds may exert their
`
`neuroprotective effects by activating cellular stress-response pathways, including
`
`the Nrf2 pathway, resulting in the upregulation of neuroprotective genes.
`
`However, the exact mechanism of action of these compounds remains poorly
`
`understood.
`
`[0008] To date, more than 10 different chemical classes of inducers of
`
`Nrf2 pathway have been identified including isothiocyanates and their thiol
`
`addition products, dithiocarbamates, as well as 1 ,2-dithiole-3-thiones, trivalent
`
`arsenic derivatives (e.g., phenyl arsenoxide), heavy metals, certain conjugated
`
`cyclic and acyclic polyenes (including porphyrins, chlorophyllins, and chlorophyll),
`
`and vicinal dimercaptans. These inducers have few $tructural similarities. They
`
`are mostly electrophiles, and all can react chemically with thiol groups by
`
`alkylation, oxidation, or reduction, suggesting that the intracellular sensor for
`
`inducers is likely to contain very highly reactive (cysteine) thiols. The inducers
`
`can modify thiol groups by a variety of mechanisms including: alkylation (Michael
`addition acceptors, isothiocyanates, qu!nones); oxidation~e.g., peroxides and
`hydroperoxides); and direct reaction with thiol/disulfide linkages (e.g., vicinal
`
`dithiols such as 1,2-dimercaptopropanol, lipoic acid). These diverse response
`
`3
`
`Page 10 of 49
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`Attorney Docket No, 08201.6042~00000
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`mechanisms provide plasticity for cellular responses to a variety of electrophiUc
`
`and oxidant stressors,
`
`[0009] There is a need to develop new treatments, and in particular,
`
`compounds for treating MS that provide neuroprotection. The development of
`
`cell~based and in vitro assays to identify and characterize existing drug
`
`candidates serves this goal.
`
`[0010]
`
`In some embodiments, the invention provides the following
`
`methods:
`
`1) methods of screening for new candidate compounds that may be
`
`useful for treating a neurological disease;
`
`2) methods of evaluating neuroprotective properties of drugs and drug
`
`candidates for treating a neurological disease;
`
`3) methods of comparing (e.g" for bioequivalence) two or more
`
`pharmaceutical compositions which contain fumaric acid derivatives;
`
`4) methods of treating a neurological disease by administering to the
`
`subject in need thereof compounds that are partially structurally
`
`similar to DMF or MMF; and
`
`5) methods of treating a neurological disorder by a combination therapy
`
`that includes administration of a first compound that upregulates the
`
`Nrf2 pathway and a second compound that does not upregulate the
`
`Nrf2 pathway.
`
`[0011] A neurological disease in methods 1 ~5 above is preferrably a
`
`neurodegenerative disease such as, for example, ALS, Parkinson's disease,
`
`Alzheimer's diseas~, and Huntington's disease, More preferably, the
`
`neurological disease is MS or another demyelinating neurological disease,
`
`[0012] Methods 1 ~3 of the invention may comprise:
`
`a) contacting a cell with the test compound, and
`.
`b) determining whether the ~rf2 pathway is upregulated in the cell .
`In some embodiments, the methods may further comprise:
`
`4
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`Page 11 of 49
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`Attorney Docket No. 08201.6042-00000
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`c) determining whether the test compound slows or prevents
`
`demyelination, axonal loss, and/or neuronal death, and/or
`
`d) selecting the test compound as a candidate for treating
`
`neurodegeneration in a neurological disease if 1) the Nrf2 pathway is
`
`upregulated and 2) demyelination, axonal loss, and/or neuronal death
`
`are/is prevented or slowed.
`
`[0013] Methods 1-3 of the invention comprise contacting a cell with test
`
`compound(s) and determining whether the Nrf2 pathway is upregulated in the
`
`cell. In such methods, an upregulation of the Nrf2 pathway above a threshold
`
`(e.g., by at least 30% over a control) indicates that the compound(s) has/have
`
`certain biological properties beneficial in treating a neurological disease (e.g.,
`
`neuroprotective properties). In some embodiments, the upregulation of the Nrf2
`
`pathway is assessed (in vivo and/or in vitro) by one or more of the following:
`
`i) expression levels of endogenously produced or exogenously
`
`introduced Nrf2;
`
`ii) subcellular localization and/or nuclear translocation of Nrf2;
`
`iii) expression levels and/or activity of one or more genes under control
`
`of Nrf2 (e.g., endogenous NQ01) or an Nrf2-regulated reporter gene
`
`in an artificial reporter construct;
`
`iv)
`
`levels of Nrf2 binding to the Nrf2-binding DNA element ARE;
`
`v) stability of Nrf2lKeap1 complexes; and
`
`vi) modification (e.g., alkylation) levels of Keap1 and other
`
`Nrf2lKeap1-associated proteins.
`
`[0014]
`
`In some embodiments of methoQs 1-3, the compounds that are
`
`being screened, evaluated, or compared are mild alkylating agents, and more
`
`specifically, Michael addition acceptors, or compounds that are metabolized upon
`
`administration to Michael addition acceptors. In some embodiments, such
`
`Michael addition acceptors have the st~ucture of Formula I, II, III, or IV set forth in
`
`the Detailed Description.
`
`5
`
`Page 12 of 49
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`Attorney Docket No. 08201.6042-00000
`
`[0015]
`
`In certain embodiments of method 1, the method of screening for
`
`a candidate compound for treating a neurological disease comprises:
`
`a) contacting a cell with a plurality of test compounds,
`
`b) determining whether the Nrf2 pathway is upregulated in the cell, and
`
`c) selecting from the plurality of compounds at least one compound that
`
`upregulates the Nrf2 pathway,
`
`wherein an up regulation of the Nrf2 pathway by the selected compound(s)
`
`indicates that the selected compound(s) may be useful for treating a neurological
`
`disease. The plurality of compounds may be represented, e.g., by a
`
`combinatorial chemical library, and the method may be performed, e.g., by
`
`high-throughput screening.
`
`[0016]
`
`In certain embodiments of method 2; the method of evaluating
`
`neuroprotective properties of a drug or drug candidate for treating a neurological
`
`disease comprises:
`
`a) contacting a cell with the drug or drug candidate, and
`
`b) determining whether the Nrf2 pathway is upregulated in the cell,
`
`wherein an upregulation of the Nrf2 pathway by the drug or drug candidate
`
`indicates that the drug or drug candidate is useful for neuroprotection in treating
`
`a human having a neurological disease.
`
`[0017]
`
`In certain embodiments of method 3, a method of comparing two
`
`or more pharmaceutical compositions (e.g., for bioequivalence) comprises:
`
`a) contacting a cell with a first composition comprising a test compound,
`
`and
`
`b) comparing the level of Nrf2 pathway upregulation in the cell by the
`
`test compound to the corresponding level of the Nrf2 pathway
`
`up regulation in a control cell treated with a second composition
`
`comprising DMF, MMF, or both.
`.
`In some embodime~ts of method 3, the test compound is fumaric
`acid, a salt thereof, or a fumaric acid derivative. In some embodiments, the first
`
`[0018]
`
`composition comprises DMF, MMF, or both. In some embodiments, the dose
`
`6
`
`Page 13 of 49
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`Attorney Docket No. 08201.6042~00000
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`and/or the formulation of the first composition differs from the dose and/or the
`
`formulation of the second composition.
`
`[0019]
`
`In some embodiments, method 3 further comprises:
`
`c) comparing at least one pharmacokinetic parameter (e,g"
`
`serum~half~life) of the first and the second compositions,
`
`[0020]
`
`In some embodiments of method 4, the method of treating a
`
`mammal having a neurological disease comprises administering to the mammal
`
`a therapeutically effective amount of a neuroprotective compound having
`
`Formula I, II, III, or IV, e,g" a fumaric acid derivative (e,g., DMF or MMF),
`
`[0021]
`
`In some embodiments of method 4, the invention provides a
`
`method of slowing or preventing neurodegeneration (more specifically, e,g"
`
`demyelination, axonal loss, and/or neuronal death) in a patient in need thereof,
`
`by administering the compound in an amount and for a period of time sufficient to
`
`slow or prevent demyelination, axonal loss, and/or neuronal death, e,g" by at
`
`least 30% relative to a control,
`
`[0022]
`
`In certain embodiments of method 5, the method of treating a
`
`mammal having a neurological disease by combination therapy comprises:
`
`a) administering to the mammal a therapeutically effective amount of a
`
`first compound that upregulates the Nrf2 pathway, and
`
`b) administering a therapeutically effective amount of a second
`
`compound that does not upregulate the Nrf2 pathway,
`
`[0023]
`
`In some of embodiments of method 5, the first compound, used in
`
`step (a), is a compound of Formula I, II, III, or IV, e,g" a fumaric acid derivative
`
`(e,g" DMF or MMF); and the second compound, which is used in step (b), is an
`
`immunosuppressive or an immunomodulatory compound that does not
`
`upregulate the Nrf2 pathway (e,g" by more than 30% over a control),
`
`[0024]
`
`In some embodiments of method 5, the method of treating a
`
`neurological disease in a mammal c6r1)prises administering to the mammal a
`
`therapeutically effective amount of a compound of Formula I, II, III, or IV.
`
`7
`
`Page 14 of 49
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`Attorney Docket No. 08201.6042-00000
`
`[0025]
`
`In some of the embodiments of methods 1-5, the compound being
`
`screened,identified, evaluated, or used for treating a neurological disorder is not
`
`fumaric acid or its salt, or a fumaric acid derivative (e.g., DMF or MMF).
`
`[0026] Other features and embodiments of the invention will be apparent
`
`from the following description and the claims.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0027] Figure 1 demonstrates that DMF and MMF are potent activators
`
`of Nrf2 at concentrations within clinical exposure range (cells in culture).
`
`[0028] Figure 2 shows results of RNAi experiments.
`
`DETAILED DESCRIPTION
`
`[0029] The present invention is based, in part, on the discovery that
`
`dimethyl fumarate (DMF) and monomethyl fumarate (MMF) are potent activators
`
`of the Nrf2 pathway, a major neuroprotective and anti-inflammatory mechanism;
`
`The invention is further based, at least in part, on the finding that DMF and MMF
`
`are neuroprotective (myelinoprotective and axonoprotective) in a mouse model of
`
`autoimmune neurodegenerative disease.
`
`[0030] Due to the involvement of Nrf2 in the regulation of cellular
`
`response to metabolic stress, survival and inflammation, DMF, MMF, and other
`
`Nrf2 activators may be useful for therapeutic management of a variety of
`
`inflammatory, ischemic, and neurodegenerative processes.
`
`[0031] Fumaric acid esters, such as DMF, have been proposed for
`treatment of MS (see, e.g., Schimrigk et aI., Eur. J. Neurol., 2006, 13(6):604-10;
`Drugs R&D, 2005, 6(4):229-30).
`
`anti-inflammatory mechanism not tarQeted by current therapies. Thus, the
`
`[0032] DMF activates a major cytoprotective (neuroprotective) and
`.
`
`findings that DMF activates the Nrf2 pathway and has a neuroprotective effect,
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`offer a rationale for the use of DMF in combination with immunosuppressive or
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`immunodulatory therapeutics that do not upregulate the Nrf2 pathway. The
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`invention further provides means for identifying compounds with a new
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`therapeutic modality useful in multiple neurological indications and
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`complementary to other drugs for the treatment of a neurological disease,
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`including a number of currently used immunomodulators.
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`[0033] DMF is a member of a large group of anti~oxidant molecules
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`known for their cytoprotective and anti~inflammatory properties. These
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`molecules also share the property of the Nrf2 pathway activation. Thus, the
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`finding that DMF activates the Nrf2 pathway in conjunction with the
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`neuroprotective effects of DMF further offers a rationale for identification of
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`structurally and/or mechanistically related molecules that would be expected to
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`be therapeutically effective for the treatment of neurological disorders, such as,
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`e.g., MS.
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`I. Definitions
`[0034] Certain terms are defined in this section; additional definitions are
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`provided throughout the description.
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`[0035] The terms "activation" and "upregulation," when used in reference
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`to the Nrf2 pathway, are used interchangeably herein.
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`[0036] The terms "disease" and "disorder" are used interchangeably
`
`herein.
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`[0037] The term "a drug for treating a neurological disease" refers to a
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`compound that has a therapeutic benefit in a specified neurological disease as
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`shown in at least one animal model of a neurological disease or in human clinical
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`trials for the treatment of a neurological disease. .
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`[0038] The term "neuroprotection" and its cognates refer to prevention or
`a slowing in neuronal degeneration, including, for example, demyelination and/or
`axonal loss, and optionally, neuronal and oligodendrocyte death. Neuroprotection
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`.
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`may occur through several mechanisms, e.g., through reducing inflammation,
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`providing neurotrophic factors, scavenging free radicals, etc. As used herein, a
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`compound is considered neuroprotective if it (1) upregulates the Nrf2 pathway
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`above a certain threshold and (2) provides neuroprotection, regardless of
`possible other mechanisms of action.
`[0039] The terms ''treatment,'' "therapeutic method," ''therapeutic
`benefits," and the like refer to therapeutic as well as prophylactic/preventative
`measures. Thus, those in need of treatment may include individuals already
`having a specified disease and those who are at risk for acquiring that disease,
`[0040] The terms ''therapeutically effective dose" and "therapeutically
`effective amount" refer to that amount of a compound which results in prevention
`or delay of onset or amelioration of symptoms of a neurological disorder in a
`subject or an attainment of a desired biological outcome, such as reduced
`neurodegeneration (e.g., demyelination, axonal loss, and neuronal death) or
`reduced inflammation of the cells of the eNS.
`
`II.
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`Methods of Evaluating Compounds
`[0041]
`In one aspect, the invention provides method of evaluating
`neuroprotective properties of test compounds, including the following methods:
`1) methods of screening for new candidate compounds that may be
`useful for treating a neurological disease;
`2) methods of evaluating neuroprotective properties of drugs and
`candidates that are used or proposed for treating a neurological
`disease;
`3) methods of comparing (e,g., for bioequivalence) two or more
`pharmaceutical compositions which contain fumaric acid
`derivatives;
`[0042] Methods 1 ~3 of the invention may comprise: .
`a) contacting a cell with the test compound,
`b) determining whether the Nrf2 pathway is upregulated in the cell,
`and, in some embodiments, additionally performing the following step(s):
`c) determining whether the \test compound slows or prevents
`demyelination, axonal loss, and/or neuronal death, and/or
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`d) selecting the test compound as a candidate for treating
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`neurodegeneration in a neurological disease if 1) the Nrf2 pathway is
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`upregulated and 2) demyelination, axonal loss, and/or neuronal death
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`are/is prevented or slowed.
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`[0043] Methods 1-3 are described in detail below.
`
`Method 1: Methods of screening
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`[0044] The invention provides methods of screening for a candidate
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`compound for treating a neurological disease. Such methods comprise:
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`a) contacting a cell with a plurality of test compounds,
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`b) determining whether the Nrf2 pathway is u'pregulated in the cell, and
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`c) selecting from the plurality of compounds at feast one compound that
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`upregulates the Nrf2 pathway,
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`wherein an upregulation of the Nrf2 pathway by the selected compound(s)
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`indicates that the selected compound(s) maybe useful for treating a neurological
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`disease. For example, the plurality of compounds may be represented by a
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`combinatorial chemical library, and the screening method may be performed by a
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`high-throughput screening as described in, e.g., High-Throughput Screening in
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`Drug Discovery (Methods and Principles in Medicinal Chemistry), by Jorg Huser
`(ed.), John Wiley & Sons (2006).
`
`[0045] Combinatorial libraries of compounds are also described in, e.g.,
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`Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight
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`Compound Libraries (Tetrahedron Organic Chemistry) Ian Salusbury (ed.),
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`Elsevier (1998); Combinatorial Libraries: Synthesis, Screening and Application
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`Potential (Library Binding), by Riccardo Cortese (ed.), Walter de Gruyter (1995).
`
`The libraries of compounds may be, for example, quinone libraries and other
`libraries as described in Mittoo, Comb. Chern. & High Throughput Screen, 2006,
`9:421-423.
`
`[0046]
`
`In some embodiments, tHe .compounds that are being screened
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`and/or selected comprise at least one or a plurality of mild alkylating agents, and
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`more particularly, Michael addition acceptors or compounds that are metabolized
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`to Michael addition acceptors, including compounds of Formulas I, II, III, or IV.
`
`[0047]
`
`In some of the embodiments, the compounds comprise fumaric
`
`acid, its salt(s), and/or fumaric acid derivative(s).
`
`Methods 2: Methods of evaluating drugs and drug candidates
`
`[0048] The invention further provides methods of evaluating.
`
`neuroprotective properties of a drug or drug candidate for treating a neurological
`
`disease. Such methods comprise:
`
`a) contacting a cell with the drug or drug candidate, and
`
`b) determining whether the Nrf2 pathway is upregulated in the cell,
`
`wherein the upregulation of the Nrf2 pathway by the drug or drug candidate
`
`indicates that the drug or drug candidate is neuroprotective in treating a human
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`having a neurological disease.
`
`[0049]
`
`In some embodiments, the upregulation of the Nrf2 pathway by
`
`the drug or drug candidate indicates that the drug or drug candidate has the
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`ability to slow demyelination, the loss ofaxons, and/or neuronal death.
`
`[0050]
`
`In some embodiments, the method of evaluating a drug or drug
`
`candidate comprise an additional step:
`
`c) evaluating demyelination, loss ofaxons, and/or neuronal death.
`
`[0051]
`
`In some embodiments, steps a) and c) are performed in vivo in at
`
`least one model of a neurological disease, e.g., as described below.
`
`[0052]
`
`In other embodiments, particularly those in which the neurological
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`disease is multiple sclerosis or another demyelinating disease, the evaluated
`
`drug or drug candidate for a neurological disease is chosen from the following:
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`FTY720 (2-( 4-octylphenethyl}-2-aminopropane-1 ,3-diol; Novartis); anti-IL 12
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`antibody (e.g., ABT-874; Abbott Laboratories); GSK683699 (GSK/Tanabe);
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`NeuroVax (Immune Response Corp.; Darlington, Curro Opin. Mol. Ther., 2005,
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`7(6):598-603); anti-CCR2 antibody (e.g., M~N 1202; Millennium); interferon J3-1a
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`(e.g., AvoneX®; Biogen Idec); anti-a4-integrin antibody (e.g., Tysabri®; Biogen
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`Idec/Elan); anti-CD20 antibody (e.g., Rituxan® (Biogen Idec/Genentech);
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`TV 5010 (Teva); NBI-788 (Neurocrine); MBP8298 (BioMS (see Warren et aI.,
`Eur. J. Neurol., 2006, 13(8):887-95); Mylinax (Oral Cladribine;
`2-chlorodeoxyadenosine; SeronoIlVAX); Teriflunomide
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`«Z)-2-cyano-N-(4-(trifluoromethyl)phenyl)-3-hydroxybut-2-enamide;
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`Sanofi-Aventis); Temsirolimus (Wyeth); Laquinimod
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`(5-chloro-N-ethyl-1 ,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenylquinolin