US20110269764A1 - Therapeutic approaches for treating alzheimer disease and related disorders through a modulation of synapse function - Google Patents

Therapeutic approaches for treating alzheimer disease and related disorders through a modulation of synapse function Download PDF

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US20110269764A1
US20110269764A1 US12/915,722 US91572210A US2011269764A1 US 20110269764 A1 US20110269764 A1 US 20110269764A1 US 91572210 A US91572210 A US 91572210A US 2011269764 A1 US2011269764 A1 US 2011269764A1
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zonisamide
phenformin
drug
composition
disease
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Daniel Cohen
Ilya Chumakov
Serguei Nabirochkin
Oxana Guerassimenko
Nathalie Cholet
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Pharnext SA
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Assigned to PHARNEXT reassignment PHARNEXT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHOLET, NATHALIE, CHUMAKOV, LLYA, COHEN, DANIEL, NABIROCHKIN, SERGUEI
Publication of US20110269764A1 publication Critical patent/US20110269764A1/en
Priority to US14/954,388 priority patent/US10350195B2/en
Priority to US16/433,097 priority patent/US10874644B2/en
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to compositions and methods for the treatment of Alzheimer's disease (AD) and related disorders.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • dysphasia language disorder in which there is an impairment of speech and of comprehension of speech
  • dyspraxia disability to coordinate and perform certain purposeful movements and gestures in the absence of motor or sensory impairments
  • agnosia ability to recognize objects, persons, sounds, shapes, or smells attributable to involvement of the cortical association areas.
  • Special symptoms such as spastic paraparesis (weakness affecting the lower extremities) can also be involved (1-4).
  • AD Alzheimer disease
  • AD is at present the most common cause of dementia. It is clinically characterized by a global decline of cognitive function that progresses slowly and leaves end-stage patients bound to bed, incontinent and dependent on custodial care. Death occurs, on average, 9 years after diagnosis (5).
  • AD Alzheimer's disease
  • Memory impairment is the early feature of the disease and involves episodic memory (memory for day-today events). Semantic memory (memory for verbal and visual meaning) is involved later in the disease. By contrast, working memory (short-term memory involving structures and processes used for temporarily storing and manipulating information) and procedural memory (unconscious memory that is long-term memory of skills and procedure) are preserved until late. As the disease progresses, the additional features of language impairment, visual perceptual and spatial deficits, agnosias and apraxias emerge.
  • AD amyloid plaques containing beta-amyloid (Abeta), neurofibrillary tangles (NFT) containing Tau and neuronal and synaptic dysfunction and loss (9-11).
  • Abeta beta-amyloid
  • NFT neurofibrillary tangles
  • Tau Tau
  • neuronal and synaptic dysfunction and loss (9-11).
  • Amyloid cascade hypothesis states that the neurodegenerative process is a series of events triggered by the abnormal processing of the Amyloid Precursor Protein (APP) (12), and the “neuronal cytoskeletal degeneration hypothesis” (13), which proposes that cytoskeletal changes are the triggering events.
  • APP Amyloid Precursor Protein
  • 13 neuroneuronal cytoskeletal degeneration hypothesis
  • the most widely accepted theory explaining AD progression remains the amyloid cascade hypothesis (14-16) and AD researchers have mainly focused on determining the mechanisms underlying the toxicity associated with Abeta proteins.
  • amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the GABAergic terminals (11).
  • the purpose of the present invention is to provide new therapeutic approaches for treating AD and related disorders.
  • the inventors have identified a molecular pathway which is involved in the genesis of AD and offers novel targets for development of new treatments to ameliorate AD and related disorders, particularly for the development of combination therapies using novel or existing molecules previously used in other indications. More particularly, the inventors have identified several drugs which, alone or in combination(s), can effectively affect such pathway and represent a new and effective therapy for the treatment of AD and related disorders.
  • the invention therefore provides novel compositions and methods for treating AD disease and related disorders.
  • compositions suitable for treating Alzheimer's disease or a related disorder in a subject in need thereof wherein said compositions comprise a drug that ameliorates synapse function.
  • a further object of this invention relates to compositions suitable for treating Alzheimer's disease or a related disorder in a subject in need thereof, wherein said compositions comprise a combination of at least two drugs that ameliorate synapse function, for combined, separate or sequential administration.
  • the drug or drugs that ameliorate synapse function bind to or modulate the activity of a protein encoded by a gene selected from ABAT, ABI1, ABL1, ADORA2A, ADORA2B, AKT, AMPK, ANKRA, APBA1, ARHGAP26, ATG5, BASSOON, BDNF, BECLIN1, BIN1, BK channels (KCNMA1, KCNMB1), CACNA1C, CACNA2D3, CACNA2D4, CADPS2, CALCINEURIN, CALMODULIN, CASK, CASR, CAST, CBL, CDC2, CDC42, CDC42BPB, CDC42EP3, CDH13, CDH2, CDK5, CITRON, CNGB3, CORTACTIN, CRAM, CREB, CRMP, CTNNB1, DAB1, DCC, DEPDC2, DHFR, DLG2, DYN1, DYN3, EDNRA, ENDOPHILIN, EPHA3, EPHBR, EP
  • drugs include, without limitation, compounds selected from acamprosate, alendronate, alfentanil, amiloride, amlodipine, argatroban, aztreonam, baclofen, buclizine, bumetanide, buprenorphine, lidocaine, chlorzoxazone, cilostazol, cinacalcet, dasatinib, desirudin, dyphylline, eletriptan, ergotamine, flunitrazepam, fosphenytoin, imatinib, ketotifen, milrinone, nitroprusside, pegaptanib, pentazocine, phenobarbital, phenformin pregabalin, propylthiouracil, sulfisoxazole, tadalafil, temazepam, terbinafine, tiagabine, topiramate, triamterene, vigabatrin and zonis
  • compositions of this invention further comprise at least one drug that modulates angiogenesis, for combined, separate or sequential use.
  • compositions of this invention may further comprise at least one drug that modulates cell stress response, for combined, separate or sequential use.
  • compositions of this invention typically further comprise a pharmaceutically acceptable carrier or excipient.
  • a further object of this invention resides in a method of producing a drug for treating Alzheimer's disease or a related disorder, the method comprising a step of testing a candidate drug for activity on synapse function and selecting candidate drugs that ameliorate synapse function.
  • the invention also relates to a method of producing a composition for treating Alzheimer's disease or a related disorder, the method comprising preparing a combination of a drug that modulates synapse function and a drug that modulates angiogenesis or cell stress response, and formulating said combination of drugs for simultaneous, separate or sequential administration thereof to a subject in need thereof.
  • the invention further relates to a method of treating Alzheimer's disease or a related disorder, the method comprising simultaneously, separately or sequentially administering to a subject in need thereof a drug or a combination of drugs that ameliorate synapse function.
  • the invention further relates to a method of treating Alzheimer's disease or a related disorder, the method comprising simultaneously, separately or sequentially administering to a subject in need thereof a drug that modulates synapse function and a drug that modulates angiogenesis and/or a drug that modulates cell stress response.
  • the invention further relates to the use of a drug that ameliorates synapse function for the manufacture of a medicament for treating Alzheimer's disease or a related disorder.
  • the invention further relates to the use of a combination of at least two drugs that ameliorate synapse function for the manufacture of a medicament for treating Alzheimer's disease or a related disorder, wherein said at least two drugs are administered together, separately or sequentially.
  • the above therapies and combination therapies provide novel and effective approaches for treating AD in human subjects.
  • FIG. 1 Effect of selected drugs on neurites outgrowth in beta-amyloid intoxicated rat primary cortical neuron culture. : p ⁇ 0.01; ; p ⁇ 0.00001: significantly different from vehicle. *: p ⁇ 0.05; ****: p ⁇ 0.0001: significantly different from Abeta 25-35 . Bilateral Student's t test.
  • FIG. 2 Effect of Phenformin drugs on neurites outgrowth in beta-amyloid intoxicated rat primary cortical neuron culture. : p ⁇ 0.01: significantly different from vehicle. *: p ⁇ 0.05; **: p ⁇ 0.001: significantly different from A ⁇ 25-35 . Bilateral Student's t test.
  • a ⁇ 25-35 20 ⁇ M produces a significant intoxication, above 25%, compared to vehicle-treated neurons ( FIGS. 1-A and B and FIG. 2 ).
  • This intoxication is efficiently prevented by BDNF at 10 ng/ml (positive control).
  • the intoxication is also significantly prevented by Acamprosate ( FIG. 1A ), Zonisamide ( FIG. 1B ), and Phenformin ( FIG. 2 ).
  • FIG. 3 Effect of selected drugs pre-treatment on LDH release in human A ⁇ 1-42 toxicity on rat primary cortical cells.
  • a ⁇ 1-42 produces a significant intoxication compared to vehicle-treated neurons.
  • the present invention provides new therapeutic approaches for treating AD or related disorders.
  • the invention discloses novel use of drugs or drug combinations which allow an effective correction of such diseases and may be used for patient treatment.
  • AD related disorder designates Alzheimer's disease (AD), senile dementia of AD type (SDAT), Parkinson's disease, Lewis body dementia, vascular dementia, mild cognitive impairment (MCI), age-associated memory impairment (AAMI) and problem associated with ageing, post-encephalitic Parkinsonism, ALS and Down syndrome.
  • treatment includes the therapy, prevention, prophylaxis, retardation or reduction of symptoms provoked by the disorder.
  • treatment includes in particular the control of disease progression and associated symptoms.
  • synapse function includes any increase in the synapse function as compared to the existing function in the subject. Such amelioration may include a restoration, i.e., to normal levels, or lower increase, which are still sufficient to improve the patient condition. Such an amelioration can be evaluated or verified using known biological tests, such as described in the experimental section.
  • the term “combination” designates a treatment wherein at least two or more drugs are co-administered to a subject to cause a biological effect.
  • the at least two drugs may be administered together or separately, at the same time or sequentially.
  • the at least two drugs may be administered through different routes and protocols. As a result, although they may be formulated together, the drugs of a combination may also be formulated separately.
  • the invention relates to compositions and methods for treating Alzheimer's disease or a related disorder in a subject in need thereof, using a drug or a combination of drugs that ameliorate synapse function.
  • the inventors were able to establish that the network responsible for synapse dysfunction is a major functional network affected in Alzheimer's disease.
  • synaptic loss is a functionally-relevant hallmark of Alzheimer's disease, which ultimately leads to progressive cognitive decline, memory loss and dementia.
  • synaptic loss correlates better with cognitive deficit characterized Alzheimer pathology, compared to other AD-specific cellular lesion markers manifested in development of neurofibrillary tangles or deposition of amyloid plaques. Consequently, synapse organization and synaptic plasticity represent an important target for therapeutic interventions in the context of Alzheimer's disease.
  • APP protein is axonally transported and processed in presynaptic terminals, leading to high accumulation of Abeta at synapses. Oligomers of Abeta42 as well as amyloid plaques themselves are important for inhibiting long-term potentiation and are primarily responsible for memory impairment in AD patients.
  • the present invention thus relates to compositions and methods using drugs that ameliorate the activity of proteins involved in post-synaptic density.
  • the DLG2 gene encodes MAGUK family protein that creates an interface between clustered membrane-bound receptors, cell-adhesion molecules and actin-based cytoskeleton.
  • DLG2/PSD95 proteins complex at excitatory synapses—namely, ErbB4 and TrkB receptors processed and functionally regulated by presenilin (17-18), ionotrophic glutamate receptors of kainate (GRIK2) and NMDA types (GRIN3A, GRIN2B), delta type (GRID1, GRID2) glutamate receptors, and G-protein-coupled metabotropic glutamate receptors (GRM3, GRM7, and GRM8).
  • effector/modulator proteins that are involved in downstream signalling of the synaptic receptors—citron, a Rho/Rac effector protein, RASGRF2 linking AMPA receptors to activation of RAS/ERK kinases, PARK2 and YES1 kinase.
  • AD-relevant functionally important genes revealed by our analysis include presynaptic ⁇ -Neurexin (NXR3) and postsynaptic neuroliginl (NLGN1) proteins that form functional complex involved in dynamic co-regulation of pre- and postsynaptic membranes at excitatory synapses.
  • NXR3 presynaptic ⁇ -Neurexin
  • NLGN1 postsynaptic neuroliginl
  • PSD proteins potentially implicated in Alzheimer's disease is enriched by receptors participating in organization of excitatory glutamatergic synapses; only a few inhibitory neuronal receptors—GABA(A) and GABA(B)—were detected by our data mining screen.
  • the present invention relates to compositions and methods using drugs that ameliorate the activity of proteins involved in the regulation of neurotransmitter release, preferably at the pre-synaptic membrane.
  • neurotransmitters at a restricted and highly specialized active zone of the presynaptic plasma membrane is triggered by action potential and is controlled by combined and opposite actions of voltage-dependent, calcium-selective Ca v channels (positive modulators of neurotransmitter release) and of MaxiK channels, large conductance, voltage and calcium-sensitive potassium channels (negative modulators of neurotransmitter release). Both types of channels were selected by our analysis as pertinent therapeutic targets for treatment of Alzheimer's disease. Additionally, neurotransmitter release at presynaptic membrane could be modulated by simultaneous application of drugs influencing activity of the PRKG1 kinase and/or presynaptic GABA(B) receptors
  • the present invention relates to compositions and methods using drugs that ameliorate the activity of proteins involved in the regulation of axon growth and guidance.
  • Proteins participating in regulation of axon growth and guidance allow neuronal precursor cells and axons to migrate toward proper destinations to ensure correct location and connectivity; they are also involved in developmental maturation of newly established synapses as well as degradation of axons and synopsis in AD disease. These processes play a fundamental role for execution of cognitive functions and seem to be extremely vulnerable to toxic effect of Abeta depositions.
  • Consecutive steps of axon growth and guidance are tightly controlled by combined actions of extracellular or membrane-tethered Netrins, Semaphorins, Ephrins, DLL and Slits molecules and their respective functional receptors, most of which were revealed by our data mining approach.
  • Functional outcomes of activation of most of axon growth receptors are tightly connected with their ability to differentially modulate activity of small GTPases RhoA, Rac1 and Cdc42, with the RhoA GTPase being mainly responsible for neurite retraction and growth cone collapse (19).
  • DCC axon guidance Netrin receptor is involved both in neurons attraction and repulsion, while UNC5C netrin receptor rather possesses neuron repulsion activity (20); semaphorins and ephrins mediate growth cones collapse and repulsion in nervous system during development and play an important role in synaptic plasticity in adult CNS (21-25). Slits proteins are involved simultaneously to axons repulsion and branching, two tightly linked processes, and modulate activity of netrin receptors (26). Finally, Notch receptor seems to affect axon guidance through both RBPJ-dependent and RBPJ-independent ABL1/DAB1/TRIO pathway controlling organization of actin cytoskeleton (27).
  • compositions and methods of this invention use drugs that ameliorate synapse function through their interaction with or modulation of one gene or protein as listed above.
  • compositions of this invention comprise a drug or drugs that ameliorate synapse function through binding to or modulating the activity of a protein encoded by a gene selected from ABAT, ABI1, ABL1, ADORA2A, ADORA2B, AKT, AMPK, ANKRA, APBA1, ARHGAP26, ATG5, BASSOON, BDNF, BECLIN1, BIN1, BK channels (KCNMA1, KCNMB1), CACNA1C, CACNA2D3, CACNA2D4, CADPS2, CALCINEURIN, CALMODULIN, CASK, CASR, CAST, CBL, CDC2, CDC42, CDC42BPB, CDC42EP3, CDH13, CDH2, CDK5, CITRON, CNGB3, CORTACTIN, CRAM, CREB, CRMP, CTNNB1, DAB1, DCC, DEPDC2, DHFR, DLG2, DYN1, DYN3, EDNRA, ENDOPHILIN, EP
  • the invention further describes drugs that can be used to modulate these target genes and proteins.
  • the invention discloses the identification and activity of particular drugs which, either alone but preferentially in combination(s), modulate the above pathway and may be used to treat said diseases.
  • drugs which, either alone but preferentially in combination(s), modulate the above pathway and may be used to treat said diseases.
  • we identified small molecules which already exist in the literature but being used to treat distinct diseases in human subjects.
  • compositions of this invention comprise at least an inhibitor of ABAT (preferably, vigabatrin); and/or an inhibitor of ABL1 (preferably imatinib); and/or a modulator of ADORA2B (preferably dyphylline); and/or a modulator of AMPK (preferably phenformin) and/or an inhibitor of CACNA1C (preferably amlodipine); and/or an inhibitor of CACNA2D3 (preferably pregabalin); and/or a modulator of CASR (preferably cinacalcet); and/or a modulator of CNGB3 (preferably amiloride), and/or an inhibitor of DHFR (preferably triamterene), and/or an inhibitor of EPHA3 (preferably dasatinib), and/or antagonist of EDNRA endothelin receptor (preferably sulfisoxazole), and/or a modulator of GABBR2 and glutamatergic receptors (preferably selected from baclofen and a
  • the invention particularly proposes to design combination therapies to address the mechanisms of AD and related disorders.
  • examples of most preferred target and drug combinations are disclosed below.
  • composition of the invention comprises at least one of the following combinations of drugs, for combined, separate or sequential administration:
  • compositions of this invention comprise a compound selected from acamprosate, alendronate, alfentanil, amiloride, amlodipine, argatroban, aztreonam, baclofen, buclizine, bumetanide, buprenorphine, lidocaine, chlorzoxazone, cilostazol, cinacalcet, dasatinib, desirudin, dyphylline, eletriptan, ergotamine, flunitrazepam, fosphenytoin, imatinib, ketotifen, milrinone, nitroprusside, pegaptanib, pentazocine, phenformin, phenobarbital, pregabalin, propylthiouracil, sulfisoxazole, tadalafil, temazepam, terbinafine, tiagabine, topiramate, triamterene, vigabatrin and zon
  • combination therapies of this invention comprise the combined use of at least the following compounds:
  • compositions of this invention comprise at least one compound chosen from the group consisting of zonisamide, dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof.
  • compositions according to the invention comprise zonisamide, or a salt or a prodrug or a derivative or a sustained release formulation thereof, for treating Alzheimer's disease (AD) in a subject in need thereof.
  • AD Alzheimer's disease
  • compositions of the invention comprise a combination of at least two compounds chosen from the group consisting of zonisamide, dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof, for simultaneous, separate or sequential administration.
  • the composition according to the invention comprises a combination of at least two compounds chosen from the group consisting of zonisamide, dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof, wherein said composition ameliorates synapse function altered in neurodegenerative disorders selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS).
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • ALS Amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • the composition of the invention comprises a combination of at least two compounds chosen from the group consisting of zonisamide, dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof for treating Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • the composition for treating Alzheimer's disease or a related disorder in a subject in need thereof comprises at least one of the following drug combinations for combined, separate or sequential administration:
  • compositions for treating Alzheimer's disease comprise zonisamide in combination with at least one compound chosen from the group consisting of dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, phenformin, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof.
  • the composition according to the invention comprises at least zonisamide and acamprosate, or salts or prodrugs or derivatives or sustained release formulations thereof, for simultaneous, separate or sequential administration.
  • compositions for treating Alzheimer's disease comprise phenformin, salts or prodrugs or derivatives or sustained release formulations thereof, either alone or in combination with at least one compound selected from the group of zonisamide, dyphylline, tadalafil, argatroban, acamprosate, cinacalcet, terbinafine, cilostazol, baclofen, amlodipine and sulfisoxazole, or salts or prodrugs or derivatives or sustained release formulations thereof.
  • composition further comprises at least one drug that modulates synapse function, for combined, separate or sequential use.
  • the additional drug that modulates synapse function is selected from an inhibitor of ABAT (preferably, vigabatrin); and/or an inhibitor of ABL1, (preferably imatinib); and/or a modulator of ADORA2B (preferably dyphylline); and/or a modulator of AMPK (preferably, phenformin) and/or an inhibitor of CACNA1C, (preferably amlodipine); and/or an inhibitor of CACNA2D3, (preferably pregabalin); and/or a modulator of CASR (preferably, cinacalcet); and/or a modulator of CNGB3 (preferably, amiloride), and/or an inhibitor of DHFR (preferably, triamterene), and/or an inhibitor of EPHA3 (preferably, dasatinib), and/or antagonist of EDNRA endothelin receptor (preferably, sulfisoxazole), and/or a modulator of GABBR2 and glutamatergic receptors (preferably selected from ba
  • said additional drug that modulates synapse function is selected from the drug or drugs that bind to or modulate the activity of a protein encoded by a gene selected from: ABAT, ABI1, ABL1, ADORA2A, ADORA2B, AKT, AMPK, ANKRA, APBA1, ARHGAP26, ATG5, BASSOON, BDNF, BECLIN1, BIN1, BK channels (KCNMA1, KCNMB1), CACNA1C, CACNA2D3, CACNA2D4, CADPS2, CALCINEURIN, CALMODULIN, CASK, CASR, CAST, CBL, CDC2, CDC42, CDC42BPB, CDC42EP3, CDH13, CDH2, CDK5, CITRON, CNGB3, CORTACTIN, CRAM, CREB, CRMP, CTNNB1, DAB1, DCC, DEPDC2, DHFR, DLG2, DYN1, DYN3, EDNRA, ENDOPHILIN
  • the inventors have established that the above drugs and drug combinations provide improved and synergistic biological effect leading to an effective correction or normalization or functional dysregulation leading to AD and related disorders.
  • Examples of pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphate
  • Examples of pharmaceutically acceptable inorganic or organic acid addition salts are listed in e.g., J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
  • Therapy according to the invention may be performed alone or as drug combination, and/or in conjunction with any other therapy, targeting the same pathway or having distinct modes of actions. It and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital, so that the doctor can observe the therapy's effects closely and make any adjustments that are needed.
  • compositions of this invention further comprise at least one drug that modulates angiogenesis, preferably that increases angiogenesis, for combined, separate or sequential use. More preferably, said at least one drug that modulates angiogenesis is selected from albuterol, alendronate, ambrisentan, aminocaproic acid, balsalazide, becaplermin, cabergoline, clopidogrel, dihydroergotamine, eplerenone, fenoldopam, fludrocortisone acetate, gemfibrozil, hesperetin, leflunomide, L-histidine, liothyronine, marimastat, meloxicam, mepacrine, methazolamide, methimazole, montelukast, netilmicin, nitroglycerin, phenylbutyrate, pyrimethamine, sunitinib, thiethylperazine, tirofiban, topotecan, vid
  • compositions of this invention may further comprise at least one drug that modulates cell stress response, preferably that inhibits cell stress response, for combined, separate or sequential use.
  • the most preferred drugs that modulate cell stress response are selected from arabitol, mannitol, metaraminol, omeprazole, prilocaine, rapamycin, rifabutin, thioguanine and trehalose (see table 3 below).
  • the invention relates to a composition
  • a composition comprising a drug that ameliorates synapse function, a drug that increases angiogenesis, and a drug that inhibits cell stress response, for simultaneous, separate or sequential administration.
  • Other therapies used in conjunction with drug(s) or drug(s) combination(s) according to the present invention may comprise one or more drug(s) that ameliorate symptoms of Alzheimer's disease or drug(s) that could be used for palliative treatment of Alzheimer's disease.
  • said one or more drug(s) is/are selected from 3APS, AAB-001, ABT-089, ABT-126, AC-3933, ACC-001, Acetaminophen, AFFITOPE AD01, AFFITOPE AD02, alpha-lipoic acid, alpha-tocopherol, AN1792, anti-Abeta, AQW051, Aripiprazole, Atomoxetine, Atorvastatin, AVE1625, AVP-923, AZD0328, AZD3480, Bapineuzumab, BAY94-9172 (ZK 6013443), Bifeprunox, Bioperine, BMS-708163, BRL-049653, Bryostatin, CAD106, Celecoxib, CERE-110, Cerebrolysin, CHF 5074, Choline, Circadin, Citalopram, Coenzyme Q, Copper, CTS21166, Curcumin, CX516 (Ampalex), C
  • TRx0014 (methylthioninium chloride), Tryptophan, V950, Valproate, Varenicline, Vitamin C, Vitamin E, VP4896, Xaliproden, Zeaxanthin, Zolpidem, and ZT-1 (DEBIO-9902 SR).
  • compositions of the invention typically comprise one or several pharmaceutically acceptable carriers or excipients.
  • duration of the therapy depends on the stage of the disease being treated, the combination used, the age and condition of the patient, and how the patient responds to the treatment.
  • each component of the combination can be controlled independently.
  • one drug may be administered orally while the second drug may be administered intramuscularly.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side-effects.
  • the drugs may also be formulated together such that one administration delivers all drugs.
  • each drug of the combination may be by any suitable means that results in a concentration of the drug that, combined with the other component, is able to correct the functioning of pathways implicated in AD.
  • compositions include those suitable for oral, rectal, topical (including transdermal, buccal and sublingual), or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the invention further includes a pharmaceutical formulation, as herein before described, in combination with packaging material suitable for said formulations.
  • a formulation for the combination treatment can be inferred by instructions, facilities, provisions, adaptations and/or other means to help using the formulation most suitably for the treatment.
  • Such measures make a patient pack specifically suitable for and adapted for use for treatment with the combination of the present invention.
  • the drug may be contained in any appropriate amount in any suitable carrier substance, and is may be present in an amount of 1-99% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.
  • the controlled release formulations include (i) formulations that create a substantially constant concentration of the drug within the body over an extended period of time; (ii) formulations that after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time; (iii) formulations that sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance; (iv) formulations that localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; and (v) formulations that target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
  • Administration of drugs in the form of a controlled release formulation is especially preferred in cases in which the drug, either alone or in combination, has (i) a narrow therapeutic index (i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; in general, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a very short biological half-life so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index i.e., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)
  • LD50 median lethal dose
  • ED50 median effective dose
  • Controlled release may be obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner (single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes).
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhes
  • the tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period.
  • the coating may be adapted to release the active drug substance in a predetermined pattern (e.g., in order to achieve a controlled release formulation) or it may be adapted not to release the active drug substance until after passage of the stomach (enteric coating).
  • the coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).
  • a time delay material such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active drug substance).
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology.
  • drugs may be mixed together in the tablet, or may be partitioned.
  • the first drug is contained on the inside of the tablet, and the second drug is on the outside, such that a substantial portion of the second drug is released prior to the release of the first drug.
  • Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, liquid paraffin, or olive oil. Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner.
  • an inert solid diluent e.g., potato starch, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, liquid paraffin, or olive oil.
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner.
  • Controlled release compositions for oral use may, e.g., be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance.
  • Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of drugs, or by incorporating the drug into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • a controlled release composition containing one or more of the drugs of the claimed combinations may also be in the form of a buoyant tablet or capsule (i.e., a tablet or capsule that, upon oral administration, floats on top of the gastric content for a certain period of time).
  • a buoyant tablet formulation of the drug(s) can be prepared by granulating a mixture of the drug(s) with excipients and 20-75% w/w of hydrocolloids, such as hydroxyethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose. The obtained granules can then be compressed into tablets. On contact with the gastric juice, the tablet forms a substantially water-impermeable gel barrier around its surface. This gel barrier takes part in maintaining a density of less than one, thereby allowing the tablet to remain buoyant in the gastric juice.
  • Powders, dispersible powders, or granules suitable for preparation of an aqueous suspension by addition of water are convenient dosage forms for oral administration.
  • Formulation as a suspension provides the active ingredient in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives.
  • Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate, and the like.
  • the pharmaceutical composition may also be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • injection, infusion or implantation intravenous, intramuscular, subcutaneous, or the like
  • suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • compositions for parenteral use may be provided in unit dosage forms (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added (see below).
  • the composition may be in form of a solution, a suspension, an emulsion, an infusion device, or a delivery device for implantation or it may be presented as a dry powder to be reconstituted with water or another suitable vehicle before use.
  • the composition may include suitable parenterally acceptable carriers and/or excipients.
  • the active drug(s) may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, or the like for controlled release.
  • the composition may include suspending, solubilizing, stabilizing, pH-adjusting agents, and/or dispersing agents.
  • the pharmaceutical compositions according to the invention may be in the form suitable for sterile injection.
  • the suitable active drug(s) are dissolved or suspended in a parenterally acceptable liquid vehicle.
  • acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution.
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate).
  • a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
  • Controlled release parenteral compositions may be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, or emulsions.
  • the active drug(s) may be incorporated in biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices.
  • Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamnine).
  • Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies.
  • Materials for use in implants can be non-biodegradable (e.g., polydimethyl siloxane) or biodegradable (e.g., poly(caprolactone), poly(glycolic acid) or poly(ortho esters)).
  • suitable dosage forms for a composition include suppositories (emulsion or suspension type), and rectal gelatin capsules (solutions or suspensions).
  • the active drug(s) are combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols.
  • an appropriate pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols.
  • additives, enhancers, or surfactants may be incorporated.
  • compositions may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non-toxic pharmaceutical acceptable carriers and excipients including microspheres and liposomes.
  • the formulations include creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters, and other kinds of transdermal drug delivery systems.
  • the pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, and skin protective agents.
  • the Emulsifying Agents may be Naturally Occurring Gums (e.g., Gum Acacia or Gum Tragacanth)
  • the preservatives, humectants, penetration enhancers may be parabens, such as methyl or propyl p-hydroxybenzoate, and benzalkonium chloride, glycerin, propylene glycol, urea, etc.
  • compositions described above for topical administration on the skin may also be used in connection with topical administration onto or close to the part of the body that is to be treated.
  • the compositions may be adapted for direct application or for application by means of special drug delivery devices such as dressings or alternatively plasters, pads, sponges, strips, or other forms of suitable flexible material.
  • the drugs of the combination may be administered concomitantly, either in the same or different pharmaceutical formulation or sequentially. If there is sequential administration, the delay in administering the second (or additional) active ingredient should not be such as to lose the benefit of the efficacious effect of the combination of the active ingredients.
  • a minimum requirement for a combination according to this description is that the combination should be intended for combined use with the benefit of the efficacious effect of the combination of the active ingredients. The intended use of a combination can be inferred by facilities, provisions, adaptations and/or other means to help using the combination according to the invention.
  • the active drugs of the present invention may be administered in divided doses, for example two or three times daily, a single daily dose of each drug in the combination is preferred, with a single daily dose of all drugs in a single pharmaceutical composition (unit dosage form) being most preferred.
  • Administration can be one to several times daily for several days to several years, and may even be for the life of the patient. Chronic or at least periodically repeated long-term administration will be indicated in most cases.
  • pharmacogenomic the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic
  • information about a particular patient may affect the dosage used.
  • the preferred dosage of each drug in the combination usually lies within the range of doses not above those usually prescribed for long-term maintenance treatment or proven to be safe in phase 3 clinical studies.
  • each compound may be used at low doses in a combination therapy, while producing, in combination, a substantial clinical benefit to the patient.
  • the combination therapy may indeed be effective at doses where the compounds have individually no substantial effect.
  • a particular advantage of the invention lies in the ability to use sub-optimal doses of each compound, i.e., doses which are lower than therapeutic doses usually prescribed, preferably 1 ⁇ 2 of therapeutic doses, more preferably 1 ⁇ 3, 1 ⁇ 4, 1 ⁇ 5, or even more preferably 1/10 to 1/100 of therapeutic doses. At such sub-optimal dosages, the compounds alone would be substantially inactive, while the combination(s) according to the invention are fully effective.
  • a preferred dosage corresponds to amounts from 1% up to 50% of those usually prescribed for long-term maintenance treatment, for instance from 1% up to 10%.
  • the amount of the drug actually administered will be determined by a physician, in the light of the relevant circumstances including the condition or conditions to be treated, the exact composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration. Therefore, the above dosage ranges are intended to provide general guidance and support for the teachings herein, but are not intended to limit the scope of the invention.
  • AD Alzheimer's disease
  • fibrillar Abeta protein Amyloid
  • the conformational change from soluble to fibrillar forms seems to be a spontaneous event that is increased with higher concentrations of Abeta, so any production of larger amounts of Abeta than normal (or production of the larger, less soluble forms of Abeta) will tend to increase plaque formation.
  • Abeta plaque Once the Abeta plaque has started to form, other molecules can interact with the nascent plaque to produce eventually the mature plaque with its associated areas of neuronal cell death. Considering this, we have evaluated the effects of our candidate drugs on the viability of the cells exposed to the amyloid ⁇ protein.
  • rat cortical neurons are cultured as described by Singer et al., 1999. Briefly pregnant female rats of 15 days gestation are killed by cervical dislocation (Rats Wistar; Janvier) and the foetuses removed from the uterus. The cortex are removed and placed in ice-cold medium of Leibovitz (L15; Invitrogen) containing 1% of Penicillin-Streptomycin (PS; Invitrogen) and 1% of bovine serum albumin (BSA; Sigma). Cortex are dissociated by trypsinisation for 20 min at 37° C. (Trypsin EDTA 1 ⁇ ; Invitrogen) diluted in PBS without calcium and magnesium.
  • Leibovitz L15; Invitrogen
  • PS Penicillin-Streptomycin
  • BSA bovine serum albumin
  • the reaction is stopped by the addition of Dulbecco's modified Eagle's medium (DMEM; Invitrogen) containing DNAase I grade II (0.1 mg/ml; Roche Diagnostic) and 10% of foetal calf serum (FCS; Invitrogen).
  • DMEM Dulbecco's modified Eagle's medium
  • FCS foetal calf serum
  • Cells are then mechanically dissociated by 3 passages through a 10 ml pipette. Cells are then centrifuged at 180 ⁇ g for 10 min at 10° C.
  • the supernatant is discarded and the cells of pellet are re-suspended in a defined culture medium consisting of Neurobasal (Invitrogen) supplemented with B27 (2%; Invitrogen), L-glutamine (0.2 mM;Invitrogen), 1% of PS solution and 10 ng/ml of Brain-derived neurotrophic factor (BDNF, Pan Biotech).
  • Viable cells are counted in a Neubauer cytometer using the trypan blue exclusion test. Cells are seeded at a density of 30 000 cells/well in 96 well-plates (wells are pre-coated with poly-L-lysine (10 mg/ml; Sigma) and are cultured at 37° C. in a humidified air (95%)/CO2 (5%) atmosphere.
  • BDNF beta-amylo ⁇ d
  • MAP-2 microtubule associated protein 2
  • SIGMA fluorescent dye
  • results are presented in FIGS. 1 and 2 . These results are extracted from two independent cultures, 6 wells per condition. All values are expressed as mean ⁇ s.e. mean. A bilateral Student's t test analysis is performed on raw data. Results are expressed in percentage of neurites length, compared to the control (vehicle).
  • Drugs were incubated with rat primary cortical neurons one hour before Abeta 25-35 20 ⁇ M intoxication that lasts 2 days (40).
  • a ⁇ 1-42 is the full length peptide that constitutes aggregates found in biopsies from human patients afflicted with AD.
  • the drugs are first tested individually, followed by assays of their combinatorial action. The effect is determined on various cell types, to further document the activity of the compounds.
  • a ⁇ 1-42 peptide was reconstituted in define culture medium at 40 ⁇ M (mother solution) and was slowly shaked at +37° C. for 3 days in dark.
  • the control medium was prepared in the same conditions.
  • BDNF 50 ng/ml
  • Estradiol- ⁇ 100 and 150 nM
  • Estradiol- ⁇ at 100 and 150 nM were used as reference test compound and BDNF at 50 ng/ml was used as a positive control.
  • Estradiol- ⁇ and BDNF were solved in culture medium and pre-incubated for 1 h before the amyloid- ⁇ 1-42 application.
  • a ⁇ 1-42 is the full length peptide that constitutes aggregates found in biopsies from human patients that suffered from AD. To be the closest as possible of the human disease, the protection afforded by candidate compounds toward A ⁇ 1-42 was assessed.
  • HBMEC Human Brain Microvascular Endothelial Cells
  • HBMEC Human brain microvascular endothelial cerebral cells
  • ScienCell Ref 1000, frozen at passage 10
  • FCS foetal calf serum
  • CSC serum-free medium CSC serum free, Cell System, Ref: SF-4Z0-500-R, Batch 51407-4
  • Serum free RocketFuel Cell System, Ref: SF-4Z0-500-R, Batch 54102
  • Penicillin 10.000 U/ml and Streptomycin 10 mg/ml PS; Pan Biotech ref: P06-07100 batch 133080808
  • PS Pan Biotech ref: P06-07100 batch 133080808
  • a ⁇ 1-42 peptide (Bachem, ref: H1368 batch 1010533) was reconstituted in define culture medium at 20 ⁇ M (mother solution) and was slowly shacked at +37° C. for 3 days in dark.
  • the control medium was prepared in the same conditions. After 3 days, this human amyloid peptide was used on HBMEC at 2.5 ⁇ M diluted in control medium (optimal incubation time).
  • the A ⁇ 1-42 peptide was added 2 hours after HBMEC seeding on matrigel for 18 hours incubation.
  • test compounds and VEGF-165 were solved in culture medium (+0.1% DMSO) and then pre-incubated with HBMEC for 1 hour before the A ⁇ 1-42 application (in a final volume per culture well of 100 ⁇ l).
  • test compounds or VEGF incubation two hours after cell seeding on matrigel, 100 ⁇ l of A ⁇ 1-42 peptide was added to a final concentration of 2.5 ⁇ M diluted in control medium in presence of test compounds or VEGF (in a 200 ⁇ l total volume/well), in order to avoid further drug dilutions.
  • VEGF-165 known to be a pro-angiogenic isoform of VEGF-A, was used for all experiments in this study as reference compound.
  • VEGF-165 is one of the most abundant VEGF isoforms involved in angiogenesis.
  • VEGF was used as reference test compound at 10 nM.
  • Alzheimer's disease-linked mutant human amyloid beta protein precursor (APP) transgenes has been the most reliable means of promoting deposition of Abeta in the brains of transgenic mice that served as AD disease models in numerous studies. As they age, these mutant APP mice develop robust amyloid pathology and other AD-like features, including decreased synaptic density, reactive gliosis, and some cognitive deficits. Many mutant APP mouse models show little evidence of overt neuronal loss and neurofibrillary tangle (NFT) pathology. Mice hemizygous for this BRI-Abeta42 transgene are viable and fertile with a normal lifespan.
  • NFT neurofibrillary tangle
  • Transgenic BRI-Abeta42 mRNA is expressed in a pattern characteristic of the mouse prion protein promoter; highest transgene expression levels are detected in the cerebellar granule cells and hippocampus, followed by the cortex, pons, thalamus, and midbrain.
  • Abeta1-42 is fused to the C terminus of the BRI protein at the furin-like cleavage site such that cleavage results in efficient Abeta1-42 secretion into the lumen or extracellular space. Therefore, these mice specifically express the Abeta1-42 isoform.
  • Hemizygous BRI-Abeta42 mice accumulate detergent-insoluble amyloid-beta with age and develop cored plaques in the cerebellum at as early as 3 months of age.
  • Amyloid beta deposits can be observed as early as 3 months in molecular layer of cerebella of transgenic mice and becoming more pronounced with age; occasional extracellular plaques are seen in the entorhinal/piriform cortices and hippocampus at 6 months of age, but aren't consistently found until >12 months of age.
  • Oldest mice show widespread pathology with cored and diffuse plaques in cerebellum, cortex, hippocampus, and olfactory bulb.
  • Extracellular amyloid plaques show dense amyloid cores with radiating fibrils; many bundles of dystrophic neurites are observed at the periphery of these plaques. Reactive gliosis is associated with plaques.
  • mice The transgenic Tg (Prnp-ITM2B/APP695*42) A12E mc mice (31) has been obtained from Jackson Laboratory (http://jaxmice.jax.org/strain/007002.html). Mice founder with the highest Abeta42 plasma levels, line BRI-Abeta42A (12e), have been maintained on a mixed B6C3 background.
  • Adult male transgenic mice have free access to food and water. In accord with an approved the Institutional Animal Care and Use Committee protocol, mice have been weighed and injected i.p. or force fed once daily for 10 to 20 consecutive weeks with either a control solution (placebo) or PXT drugs, prepared at different doses.
  • This experiment is performed in a circular pool, 90 cm in diameter, made of white plastic and filled with milky colored water.
  • An escape platform, 8 cm in diameter, made of clear plastic was submerged 0.5 cm under the water level.
  • Visual clues are provided by different geometrical forms printed in A4-sized letters and placed on the four surrounding walls (distance from the pool was from 50 to 70 cm).
  • Each mouse has been given four trials daily (5- to 7-minute interval between trials, a total of 16 trials) for 4 days. Each trial has been performed from one of four different starting points.
  • the movement of the mice is monitored using Videotrack Software (View Point).
  • the time taken to locate the escape platform (escape latency; up to 60 seconds) has been determined After locating the platform the mouse has been allowed to sit on it for 15 seconds.
  • mice who failed to find the platform within 60 seconds have been guided to it and allowed to stay on it for 15 seconds. A latency of 60 seconds is entered into the record for such an occurrence. All four trials per day have been averaged for statistical analysis, except for the first trial on day 1. On day 9 (5 days after the last training) mice have been subjected to a 60-second probe trial in which the platform is removed and the mice are allowed to search for it. The time that each animal spent in each quadrant has been recorded (quadrant search time). Several groups of male mice have been used at 3, 7, 10, and 12 months. The some few mice have showed freezing behaviour (eg, lying motionless in the water and refusing to swim) that strongly interfered with the test, these animals have been excluded from the data analysis. All behavioural tests are conducted under a quiet and light-reduced environment.
  • This cognitive-based sensitive measure of working memory has been obtained with the help of the apparatus consisted of a 100 cm-diameter waterfilled pool (also used for the Morris water maze and Platform Recognition tasks) fitted with an aluminium insert to create six radially-distributed swim arms. Testing consists of five, 1-min trials per daily session, for 9-12 consecutive days. At the start of each session, a clear submerged platform is positioned at the end of one of the six swim arms (randomly-selected, changed daily). For each of the first four acquisition trials, the animal is placed into one of the non-platform containing arms (randomized sequence) and allowed to search for the platform.
  • This cognitive-based task test is performed with the help of the apparatus that consists of a 69 cm-diameter circular platform having 16 “escape” holes spaced equidistantly around the circumference.
  • An escape refuge is installed beneath one of the holes, and a black curtain, on which are placed various visual cues, encircles the platform.
  • the animal is placed in the center of the platform at the start of a single, 5 min trial and aversive stimuli (bright lights, fan wind) are presented.
  • the total number of errors (head-pokes into non-escape holes) and escape latency (time to reach escape hole) are recorded.
  • the target object consists of a 9 cm-diameter circular platform fitted with a 10 cm ⁇ 40 cm black ensign, which is positioned 0.8 cm above the surface of the water in a 100 cm-diameter circular pool.
  • Testing consists of four 60 s trials per day on each of four consecutive days. On each day, the target object is placed into a different quadrant of the pool for each trial, and the animal is released at the same location along the circumference of the pool for all four trials. The total latency (maximum 60 s) is recorded for each trial.
  • mice exhibited physiological, behavioural, or sensorimotor impairments related to their genotype.
  • the mice are placed on a wire that was tightened between two 30-cm-high columns and their ability to balance on the wire is assessed.
  • their ability to grasp and hang on the wire with all four paws for at least 5 seconds and to climb back on the wire is determined.
  • CAA cerebral amyloid angiopathy
  • Tg and WT mice from 3 to 12 months are anesthetized and transcardially perfused sequentially with 0.9% NaCl and 4% paraformaldehyde in 0.1 mol/L phosphatebuffered saline (PBS) (pH 7.4) or 10% formalin and 4% paraformaldehyde in 0.1 mol/L PBS (pH 7.4).
  • Brains and spinal cords are removed and stored in 4% paraformaldehyde.
  • Some samples are embedded in paraffin and cut on a sliding microtome at a thickness of 10 ⁇ m. Cryosections (14 ⁇ m) are cut on a cryostat and mounted on chrome alum-coated slides.
  • Endogenous peroxidase is quenched by treating the section with methanol containing 0.3% H2O2 for 30 minutes. Sections are blocked in 10% horse serum. Primary antibodies are used and incubated overnight at 4° C. in the presence of 1% horse serum. All secondary biotinylated or fluorescein-, Texas Red-, and AMCA-coupled antibodies, fluorochromes, ABC-kit, and 3,3′-diaminobenzidine as chromogen for peroxidase activity are from Vector Laboratories. Incubation with the secondary antibody is held at room temperature for 1 hour.
  • Brains are rapidly harvested over ice between 90 and 120 min after the final injection and frozen to ⁇ 80° C.
  • the right cerebral hemisphere from each mouse is weighed after freezing. Analysis of hemisphere mass by median absolute deviation allows us to exclude samples that are beyond 4 median absolute deviations from the rest of the set.
  • Cerebral hemispheres are homogenized, and cell lysates containing whole protein are prepared according to the manufacturer's instructions for enzymatic assay kits (R&D Systems, Inc.).
  • the brain cortices are homogenized in 800 ⁇ l of low salt containing 1 ⁇ extraction buffer (R&D kit) and incubated on ice for 10 min. The homogenates are then centrifuged at 13,000 g for 15 min at 4° C.
  • the protein concentration in each sample is estimated according to biuret-derived assay (Pierce).
  • Levels of APP, A ⁇ 40, and A ⁇ 42 are measured by Western immunoblotting and sandwich ELISA techniques, respectively, as described (28).
  • activities of ⁇ , ⁇ -, and ⁇ -secretases may be measured from the same extracts.
  • Each gel contained eight treatments: control; drug 1 7.5 mg/kg dose; and drug 2 in several doses. To minimize intra-gel variation, each gel contained three sets of all treatment groups. Each blot is probed with 22C11 antibody. Each blot is also probed with the ⁇ -actin antibody for normalization to transfer efficiency. The intensity of APP band signal is normalized with that of ⁇ -actin. Two sample “controls” are loaded in each gel/blot to test for blot to blot variation.
  • Ab9 anti-A ⁇ 1-16 Ab
  • 13.1.1-HRP anti-A ⁇ 35-40 Ab
  • Ab9-HRP Ab9-HRP
  • Snap-frozen forebrain samples are homogenized in radioimmunoprecipitation assay (RIPA) buffer (Boston BioProducts, Worcester, Mass.) with 1% protease inhibitor mixture (Roche). The homogenate is centrifuged at 100,000 ⁇ g for 1 h at 4° C. Protein concentration in supernatants is determined using the BCA protein assay (Pierce). Protein samples (20 ⁇ g) are run on Bis-Tris 12% XT gels or Bis-Tris 4-12% XT gels (Bio-Rad, Hercules, Calif.) and transferred to 0.2 ⁇ m nitrocellose membranes.
  • RIPA radioimmunoprecipitation assay
  • Blots are microwaved for 2 min in 0.1 M PBS twice and probed with Ab 82E1 (anti-A ⁇ 1-16, 1:1000; IBL, Gunma, Japan) and anti-APP C-terminal 20 amino acids (1:1000) as described (28). Blots are stripped and reprobed with anti ⁇ -actin (1:1000; Sigma) as a loading control. Relative band intensity is measured using ImageJ software.
  • a ⁇ levels, amyloid plaque burden, and CAA severity are analyzed by using ANOVA with the post hoc Holm-Sidak multiple comparison test or two-tailed Student's t test. If the data set does not meet the parametric test assumptions, either the Kruskal-Wallis test followed by the post hoc Dunn's multiple comparison or the Mann-Whitney rank sum test is performed. To test whether the A ⁇ levels in the bitransgenic mice were consistent with an additive sum of A ⁇ levels in the single transgenic littermates, a multiple linear regression with no intercept test is used. All comparisons are made between littermates.
  • Drug response modelling is done excluding the control (0 mg/kg) samples.
  • ED50 corresponds to the dose (mg/kg) required to induce a 50% of maximal drug-induced response in the experiments. It is calculated using the Hill equation model for the log of ED50.
  • Amyloid precursor protein, presenilins, and alpha-synuclein molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev. 54(3): 469-525.
  • Alzheimer's disease the amyloid cascade hypothesis. Science. 256(5054): 184-5.
  • Semaphorin III can function as a selective chemorepellent to pattern sensory projections in the spinal cord. Neuron. 14(5): 949-59.

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US10874644B2 (en) 2020-12-29
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