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WO2020107037A1 - Composés et méthodes de traitement de maladies neurodégénératives - Google Patents

Composés et méthodes de traitement de maladies neurodégénératives

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Publication number
WO2020107037A1
WO2020107037A1 PCT/US2019/063113 US2019063113W WO2020107037A1 WO 2020107037 A1 WO2020107037 A1 WO 2020107037A1 US 2019063113 W US2019063113 W US 2019063113W WO 2020107037 A1 WO2020107037 A1 WO 2020107037A1
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Prior art keywords
agent
poly
dpr
parp
composition
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WO2020107037A8 (fr
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Daniel A. MORDES
Kevin C. Eggan
Lee L. Rubin
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Harvard University
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Harvard University
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Publication of WO2020107037A8 publication Critical patent/WO2020107037A8/fr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/50—Methods for regulating/modulating their activity
    • C12N2320/53—Methods for regulating/modulating their activity reducing unwanted side-effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette

Definitions

  • ALS Amyotrophic Lateral Sclerosis
  • Lou Gehrig Lou Gehrig
  • ALS is characterized by the progressive loss of motor neurons in the brain and spinal cord resulting in severe muscle atrophy and paralysis. ALS often affects patients in their 50s with survival typically limited to just 2-5 years from the time of disease onset.
  • FDA-approved therapies for ALS, riluzole and edavarone demonstrate limited beneficial effects in select patient populations.
  • ALS is on the same disease spectrum on a related neurodegenerative disease called frontotemporal dementia (FTD).
  • FTD frontotemporal dementia
  • FTD frontotemporal dementia
  • GGGGCC hexanucleotide repeat expansion
  • C90RF72 This variant is also commonly found in patients with FTD and with both ALS and FTD.
  • DPRs dipeptide repeat proteins
  • Several DPRs have been shown to be toxic in model organisms, primary neurons, and human cell lines.
  • NGN2-cortical-like human neurons we treated this innovative translational approach to identify drug targets and potential small molecules for the treatment of C9( /i/ ' 72-ALS/FTD.
  • Some aspects of the disclosure are directed to a method of treating or preventing a neurological disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of an agent that reduces or eliminates dipeptide repeat (DPR) toxicity (e.g., GR-DPR and/or PR-DPR toxicity).
  • DPR dipeptide repeat
  • the subject has a mutation associated with production of DPR.
  • the mutation is a hexanucleotide repeat expansion (GGGGCC) mutation in the first intron of the gene C90RF72.
  • the DPR comprises poly-glycine- arginine (poly-GR) and/or poly-proline-arginine (poly-PR) dipeptide repeats.
  • the neurological disease is one or both of Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD).
  • the agent affects a pathway shown in FIG. 14.
  • the pathway is an adenosine A2A receptor, Aromatase, or PARP pathway.
  • the agent is a poly ADP ribose polymerase (PARP) inhibitor (e.g., a PARP inhibitor with CSF penetration).
  • PARP poly ADP ribose polymerase
  • the PARP inhibitor selectively inhibits one or more of PARP 1, PARP2, PARP3, PARP4, PARP9,
  • the PARP inhibitor selectively inhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 11, at least 12, at least 13 PARPs. In some embodiments, the PARP inhibitor selectively inhibits PARP1 and PARP2, PARP2 and PARP3, PARP1-PARP3, PARP1-PARP4, PARP1- PARP4 and PARP 15 -PARP 16, or PARP1-PARP4 and PARP 16.
  • the PARP inhibitor is selected from Olaparib (AZD- 2281), AZD-2461, Niraparib (MK-4827), Rucaparib (AG-14699), AG-14361, Veliparib (ABT-888), Talazoparib (BMN673), CEP 9722, E7016, BGB-290, 3-aminobenzamide (INO- 1001), NMSpl 18, A-966492, PJ34 HC1, UPF 1069, ME0328, Pamiparib (BGB-290), NMS- P118, E7449, Picolinamide, Benzamide, NU1025, Iniparib (BSI-201), Cyproterone Acetate, Exemestane, Lafutidine, CGS-21680 HC1, Entocapone, PD184352, Ouabain, BGP-15 2HC1, IKK- 16, Istradefylline, KU0058948, DPQ, NU1025, EB-47,
  • the subject is also administered a second agent to treat or prevent a neurological disease, disorder or condition.
  • the second agent is antisense oligonucleotides (ASOs) that reduce the expression of GGGGCC repeats and toxic DPRs.
  • the second agent is Edaravone or Riluzole.
  • the subject does not have TDP-43 pathology in neuronal cells. In some embodiments, the subject does not have acute TDP-43 pathology. In some embodiments, the subject is at risk for developing a neurological disease, disorder or condition (e.g., has a mutation associated with, e.g., ALS and/or FTD). In some embodiments, the agent is orally administered. In some embodiments, the subject is a human.
  • compositions comprising an agent that reduces or eliminates dipeptide repeat (DPR) toxicity in a cell.
  • DPR dipeptide repeat
  • the agent is a poly ADP ribose polymerase (PARP) inhibitor.
  • PARP poly ADP ribose polymerase
  • the composition further comprises a second agent that is antisense
  • the composition comprises a pharmaceutically acceptable excipient.
  • Some aspects of the disclosure are directed to a method of screening for a candidate agent that reduces or eliminates dipeptide repeat (DPR) toxicity in a cell, comprising providing a composition comprising neuronal cells contacted with a dipeptide repeat (DPR), contacting the composition with a test agent, comparing the viability of the neuronal cells contacted with the test agent to control neuronal cells not contacted with the test agent, and identifying a test agent as a candidate agent if the viability of the neuronal cells contacted with the test agent are increased as compared to the control neuronal cells not contacted with the test agent.
  • DPR dipeptide repeat
  • the DPR comprises poly-glycine-arginine (poly-GR) and/or poly-proline-arginine (poly-PR) dipeptide repeats.
  • the neuronal cells are stem cell-derived.
  • the neuronal cell are cortical-like neurons, upper motor neurons, or lower motor neurons.
  • the screening protocol is the screening protocol shown in FIG. 10.
  • FIGS. I A-1B show a screen of chemical modifiers of DPR toxicity.
  • FIG. I A shows a screen of stem cell-derived NGN2-cortical-like human neurons contacted with poly- glycine-arginine (poly-GR) toxic dipeptide repeats (DPR) and a commercial library of compounds. An increased viability score indicates that the compound more effectively modified poly-GR toxicity.
  • FIG. IB shows that screens of compounds against poly-GR toxicity and against poly-proline-arginine (poly-PR) toxicity using stem cell-derived NGN2- cortical-like human neurons identified 8 compounds effective against both poly-GR toxicity and poly-GR toxicity.
  • FIGS. 2A-2B show plots testing various PARP inhibitors at constant concentrations (and I 7-AAG, an Hsp90 inhibitor) in assays with stem ceil derived human neurons and toxic DPR.
  • FIG. I A shows testing with NGN2 cortical-like neurons and
  • FIG. IB show's testing with lower motor neurons (IMNs) derived from stem cells based on NGN2 expression and patterning factors.
  • INNs motor neurons
  • FIG. 3 shows a Drug Discovery and Development Timeline.
  • FIGS. 4A-4B show a small molecule screen in stem-cell derived neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Adapted from Yang et al, Cell Stem Cell , 12(6): 713-726 (2013).
  • FIG. 5 shows approved therapies for ALS.
  • FIG. 6 shows neurological manifestations of C9QRF72 hexanucleotide (GGGGCC)repeal expansion.
  • FIGS. 7A-7J show detection of dipeptide repeats in C90RF72-ALS/FTD patients. Adapted from Mon et al, Science (2013). [0018] FIG. 8 shows arginine-containing DPRs are toxic in Drosophila models. Adapted from Mizielinska et al. Science 2014.
  • FIG. 9 shows arginine-containing DPRs are toxic in Human Cortical-like Neurons.
  • FIG. 10 shows a screening protocol for finding agents that reduce or eliminate DPR toxicity in neurons.
  • FIG. 11 shows the results of a primary screen.
  • FIG. 12 is a micrograph showing control stem cell-derived neurons (left side) and stem cell-derived neurons contacted with DPR (left side), clearly showing that contact with DPR is toxic.
  • FIG. 13 shows a screen wherein stem cell-derived neurons and GR-DPR are contacted with test compounds and cell viability is measured.
  • FIG. 14 shows the pathways affected by the compounds found in the assay of FIG. 13 to reduce GR-DPR toxicity.
  • FIG. 15 shows that the adenosine A2A receptor, Aromatase, and PARP pathways each have more than one hit for compounds that reduce GR-DPR toxicity.
  • FIG. 16 shows a screen wherein stem cell-derived neurons and PR-DPR are contacted with test compounds and cell viability is measured.
  • FIG. 17 shows that the c-MET and PARP pathways each have more than one hit for compounds that reduce PR-DPR toxicity.
  • FIG. 18 shows PARP inhibitors.
  • FIG. 19 shows Velaparib is a known anti -cancer therapeutic.
  • FIG. 20 details the mechanism of action for PARP inhibitors.
  • FIG. 21 shows a secondary test of selected top compounds in NGN2 neurons at a single dose.
  • FIG. 22 shows the relative selectivity of PARP inhibitors. Adapted from Wahlberg et ak, Nature Biotechnology (2012).
  • FIG. 23 shows the expression of selected PARPs in NGN2 neurons. Adapted fromNehme et al, Cell Reports (2016).
  • FIG. 24 shows micrographs detailing increased expression of PARP 1 in ALS patient brains. Adapted from Appel et al, Neurology (2004). [0035] FIG. 25 provides proposed mechanisms for C90RF72-ALS/FTD. See Taylor JP, Nature (2016) 539(7628): 197-206.
  • FIGS. 26A-26E demonstrate identification of C90RF72-associated transcriptional changes.
  • FIG. 26A provides a diagram of RNA-seq datasets obtained from the frontal cortex and cerebellum.
  • FIG. 26B shows a comparison of the differentially expressed transcripts in C90RF72-ALS and sporadic ALS and a comparison of the differentially expressed transcripts by brain region.
  • FIG. 26C provides a correlation of the fold change of changed transcripts in C90RF72-ALS that were common to the cortex and the cerebellum.
  • FIG. 26D shows a protein chaperone network.
  • FIG. 27 demonstrates marked upregulation of HSFl-target genes in
  • FIG. 28 demonstrates selective C90RF72 DPR toxicity in stem cell-derived motor neurons.
  • FIGS. 29A-29C demonstrate DPR toxicity in NGN2 cortical-like neurons.
  • FIG. 29A provides a schematic for differentiating neurons.
  • FIG. 29B shows gene expression of MAPT and BRN2 at DO, D4, D14, and D21 of the differentiation protocol, and provides a representative image of MAP2.
  • FIG. 29C shows decrease in viability when neurons are treated with DPR.
  • FIGS. 30A-30C summarize a chemical screen for modifiers of DPR toxicity.
  • FIG. 30A shows a screen of stem cell-derived NGN2-cortical-like human neurons contacted with poly-GR DPR and a commercial library of compounds. An increased viability score indicates that the compound more effectively modified poly-GR toxicity.
  • FIG. 30B shows the pathways affected by the compounds found in the assay of FIG. 30A to reduce GR-DPR toxicity.
  • FIG. 30C shows that screens of compounds against poly-GR toxicity and against poly-PR toxicity using stem cell-derived NGN2-cortical-like human neurons identified 8 compounds effective against both poly-GR toxicity and poly-GR toxicity.
  • FIG. 31 provides an initial characterization of C90RF72-BAD mice.
  • Some aspects of the disclosure are directed to a method of treating or preventing a neurological disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of an agent that reduces or eliminates dipeptide repeat (DPR) toxicity.
  • DPR dipeptide repeat
  • Non-limiting examples of neurological disease, disorder and conditions of the present disclosure include poly glutamine expansion disorders (e.g., HD,
  • dentatorubropallidoluysian atrophy Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado-Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis (ALS), ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Guillain-Barre syndrome,
  • the neurological disease, disorder or condition is one associated with a mutation associated with production of DPR.
  • the mutation is a hexanucleotide repeat expansion (GGGGCC) mutation in the first intron of the gene C90RF72.
  • the DPR comprises poly-glycine-arginine (poly-GR) and/or poly-proline-arginine (poly-PR) dipeptide repeats.
  • the neurological disease is Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), or both ALS and FTD.
  • the neurological disease is Spinocerebellar ataxia type 36.
  • agent means any compound or substance such as, but not limited to, a small molecule, nucleic acid, polypeptide, peptide, drug, ion, etc.
  • An “agent” can be any chemical, entity or moiety, including without limitation synthetic and naturally-occurring proteinaceous and non-proteinaceous entities.
  • an agent is nucleic acid, nucleic acid analogues, proteins, antibodies, peptides, aptamers, oligomer of nucleic acids, amino acids, or carbohydrates including without limitation proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNAs, lipoproteins, aptamers, and modifications and combinations thereof etc.
  • the agent is selected from the group consisting of a nucleic acid, a small molecule, a polypeptide, and a peptide.
  • agents are small molecule having a chemical moiety.
  • chemical moieties included unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties including macrolides, leptomycins and related natural products or analogues thereof.
  • Compounds can be known to have a desired activity and/or property, or can be selected from a library of diverse compounds.
  • Small molecule is defined as a molecule with a molecular weight that is less than 10 kD, typically less than 2 kD, and preferably less than 1 kD.
  • Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing an inorganic component, molecules comprising a radioactive atom, synthetic molecules, peptide mimetics, and antibody mimetics. As a therapeutic, a small molecule may be more permeable to cells, less susceptible to degradation, and less apt to elicit an immune response than large molecules.
  • polypeptide or“protein” is used to designate a series of amino acid residues connected to the other by peptide bonds between the alpha- amino and carboxy groups of adjacent residues.
  • polypeptide refers to a polymer of protein amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function.
  • polypeptide is often used in reference to small polypeptides, but usage of this term in the art overlaps with “protein” or "polypeptide.”
  • exemplary polypeptides include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, as well as both naturally and non-naturally occurring variants, fragments, and analogs of the foregoing.
  • nucleic acid refers to polynucleotides such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • polynucleotide are used interchangeably herein and should be understood to include double-stranded
  • a nucleic acid often comprises standard nucleotides typically found in naturally occurring DNA or RNA (which can include modifications such as methylated nucleobases), joined by phosphodi ester bonds.
  • a nucleic acid may comprise one or more non-standard nucleotides, which may be naturally occurring or non-naturally occurring (i.e., artificial; not found in nature) in various embodiments and/or may contain a modified sugar or modified backbone linkage.
  • Nucleic acid modifications e.g., base, sugar, and/or backbone modifications
  • non-standard nucleotides or nucleosides, etc. such as those known in the art as being useful in the context of RNA interference (RNAi), aptamer, CRISPR technology, polypeptide production, reprogramming, or antisense-based molecules for research or therapeutic purposes
  • RNAi RNA interference
  • Such modifications may, for example, increase stability (e.g., by reducing sensitivity to cleavage by nucleases), decrease clearance in vivo, increase cell uptake, or confer other properties that improve the translation, potency, efficacy, specificity, or otherwise render the nucleic acid more suitable for an intended use.
  • nucleic acid modifications are described in, e.g., Deleavey GF, et al, Chemical modification of siRNA. Curr. Protoc. Nucleic Acid Chem. 2009; 39: 16.3.1-16.3.22; Crooke, ST (ed.) Antisense drug technology: principles, strategies, and applications, Boca Raton: CRC Press, 2008; Kurreck, J. (ed.) Therapeutic oligonucleotides, RSC biomolecular sciences. Cambridge: Royal Society of Chemistry, 2008; U. S. Patent Nos.
  • nucleic acid may be modified uniformly or on only a portion thereof and/or may contain multiple different modifications.
  • length of a nucleic acid or nucleic acid region is given in terms of a number of nucleotides (nt) it should be understood that the number refers to the number of nucleotides in a single-stranded nucleic acid or in each strand of a double-stranded nucleic acid unless otherwise indicated.
  • An“oligonucleotide” is a relatively short nucleic acid, typically between about 5 and about 100 nt long.
  • the agent is a poly ADP ribose polymerase (PARP) inhibitor.
  • PARP poly ADP ribose polymerase
  • the PARP inhibitor selectively inhibits PARPl, PARP2, or PARP3.
  • the agent selectively inhibits PARPl and PARP2, PARPl and PARP3, or PARP2 and PARP2.
  • the agent inhibits PARPl, PARP2 and PARP3.
  • the PARP inhibitor selectively inhibits one or more of PARPl, PARP2, PARP3, PARP4, PARP9, PARP10, PARP 12, PAPR13, PAPR14, PARP 15, PARP16, TNKS1, or TNKS2.
  • the PARP inhibitor selectively inhibits at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 11, at least 12, at least 13 PARPs.
  • the PARP inhibitor selectively inhibits PARPl and PARP2, PARP2 and PARP3, PARPl -PARP 3, PARP1-PARP4, PARP1-PARP4 and PARP 15 -PARP 16, or PARP1- PARP4 and PARP 16.
  • “selectively inhibits” means that the agent
  • At least one PARP preferentially inhibits at least one PARP by at least 1.1-fold, 1.2-fold, 1.3-fold, 1-4-fold, 1-5- fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 5-fold, 10-fold, or more than it inhibits another PARP.
  • the PARP inhibitor is Olaparib (AZD-2281), AZD- 2461, Niraparib (MK-4827), Rucaparib (AG-14699), AG-14361, Veliparib (ABT-888), Talazoparib (BMN673), CEP 9722, E7016, BGB-290, 3-aminobenzamide (INO-lOOl), NMSpl l8, A-966492, PJ34 HC1, UPF 1069, ME0328, Pamiparib (BGB-290), NMS-P118, E7449, Picolinamide, Benzamide, NU1025, Iniparib (BSI-201), Cyproterone Acetate, Exemestane, Lafutidine, CGS-21680 HC1, Entocapone, PD184352, Ouabain, BGP-15 2HC1, IKK- 16, Istradefylline, KU0058948, DPQ, NU1025, EB-47
  • the subject is also administered a second agent to treat or prevent a neurological disease, disorder or condition.
  • the first and second agent are co-formulated.
  • the first and second agent are administered simultaneously.
  • the first and second agent are administered within a time of each other to produce overlapping therapeutic effects in the patient.
  • the agents may be administered by the same or a different route of administration (e.g., oral versus infusion).
  • the second agent is antisense oligonucleotides (ASOs) that reduce the expression of GGGGCC repeats and toxic DPRs.
  • ASOs antisense oligonucleotides
  • “treat,”“treatment,” or“treating” when used in reference to a disease, disorder or medical condition refer to therapeutic treatments for a condition, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a symptom or condition.
  • the term“treating” includes reducing or alleviating at least one adverse effect or symptom of a condition.
  • Treatment is generally“effective” if one or more symptoms or clinical markers are reduced.
  • treatment is“effective” if the progression of a condition is reduced or halted. That is,“treatment” includes not just the improvement of symptoms or markers, but also a cessation or at least slowing of progress or worsening of symptoms that would be expected in the absence of treatment.
  • the methods described herein may lead to a reduction in the severity or the alleviation of one or more symptoms of the disorder (e.g., ALS and/or FTD).
  • a disease, disorder or medical condition refers to reducing or eliminating the likelihood of development of the disease, disorder or medical condition.
  • the term“administering,” refers to the placement of the agent as disclosed herein into a subject by a method or route which results in delivery to a site of action.
  • the agent can be administered by any appropriate route which results in an effective treatment in the subject.
  • administration via oral ingestion is specifically contemplated.
  • other routes are contemplated, including, for example, intranasally, intraarterially; intra-coronary arterially; orally, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intracavity, or by other means known by those skilled in the art.
  • the agents are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount.
  • the quantity to be administered and timing depends on the subject to be treated, capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired.
  • the agent is orally administered.
  • A“therapeutically effective amount” is an amount of an agent that is sufficient to produce a statistically significant, measurable change in, for example, blood glucose clearance. Such effective amounts can be gauged in clinical trials as well as animal studies.
  • a treatment is considered“effective treatment,” as the term is used herein, if any one or all of the signs or symptoms are improved or ameliorated, e.g., by at least 10% following treatment with an agent as described herein.
  • Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill.
  • the subject is a mouse, rat, rabbit, dog, cat, non-human primate, or human. In some embodiments, the subject is a human.
  • Some aspects of the disclosure are directed to a composition comprising an agent that reduces or eliminates dipeptide repeat (DPR) toxicity in a cell.
  • the agent may be any agent disclosed herein and is not limited.
  • the agent is a poly ADP ribose polymerase (PARP) inhibitor.
  • PARP poly ADP ribose polymerase
  • the composition comprises a second agent. The second agent may be any agent described herein and is not limited.
  • the second agent is antisense oligonucleotides (ASOs) that reduce the expression of GGGGCC repeats and toxic DPRs.
  • the composition further comprises pharmaceutically acceptable carrier, diluent, or excipient.
  • Some aspects of the disclosure are directed to a method of screening for a candidate agent that reduces or eliminates dipeptide repeat (DPR) toxicity in a cell, comprising providing a composition comprising neuronal cells contacted with a dipeptide repeat (DPR), contacting the composition with a test agent, comparing the viability of the neuronal cells contacted with the test agent to control neuronal cells not contacted with the test agent, and identifying a test agent as a candidate agent if the viability of the neuronal cells contacted with the test agent are increased as compared to the control neuronal cells not contacted with the test agent.
  • DPR dipeptide repeat
  • the DPR comprises poly-glycine-arginine (poly-GR) and/or poly-proline-arginine (poly-PR) dipeptide repeats.
  • the neuronal cells are stem cell-derived.
  • the stem cells are induced pluripotent stem cells (iPS).
  • the iPS cells are derived from a subject having a neurological disease, disorder or condition (e.g., ALS and/or FTD).
  • the neuronal cells are derived from stem cells via an NGN2 induction protocol (see, e.g., Nehme et al., Cell Reports, Vol. 23, pp. 2509-2523 (2016)).
  • the neuronal cell are cortical-like neurons, upper motor neurons, and/or lower motor neurons.
  • Methods of determining viability of a cell are not limited and may be any method known in the art.
  • the method for measuring viability is tryphan blue dye exclusion.
  • the method of screening is a high-throughput screening method.
  • “decrease,”“reduce,”“reduced,”“reduction,”“decrease,” and “'inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference.
  • “reduce,”“reduction” or“decrease” or“inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given
  • the terms“increased,”“increase” or“enhance” or“activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms“increased”,“increase” or“enhance” or“activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or more as compared to a reference level.
  • compositions, methods, and respective component(s) thereof are used in reference to compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
  • the term“consisting essentially of’ refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment.
  • the terms“protein”, and“polypeptide” refer to a polymer of protein amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function.“Protein” and“polypeptide” are often used in reference to relatively large polypeptides, whereas the term“peptide” is often used in reference to small polypeptides, but usage of these terms in the art overlaps.
  • the terms“protein” and“polypeptide” are used interchangeably herein when refining to a gene product and fragments thereof.
  • exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.
  • Claims or descriptions that include“or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes embodiments that relate analogously to any intervening value or range defined by any two values in the series, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum.
  • Numerical values include values expressed as percentages. For any embodiment of the invention in which a numerical value is prefaced by“about” or“approximately”, the invention includes an embodiment in which the exact value is recited. For any embodiment of the invention in which a numerical value is not prefaced by“about” or“approximately”, the invention includes an embodiment in which the value is prefaced by“about” or“approximately”.
  • “Approximately” or“about” generally includes numbers that fall within a range of 1% or in some embodiments within a range of 5% of a number or in some embodiments within a range of 10% of a number in either direction (greater than or less than the number) unless otherwise stated or otherwise evident from the context (except where such number would impermissibly exceed 100% of a possible value). It should be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one act, the order of the acts of the method is not necessarily limited to the order in which the acts of the method are recited, but the invention includes embodiments in which the order is so limited. It should also be understood that unless otherwise indicated or evident from the context, any product or composition described herein may be considered“isolated”.
  • ASOs antisense oligonucleotides
  • GGGGCC hexanucleotide
  • Carriers of the C90RF72 expansion can also present with frontotemporal dementia (FTD) and atypical Parkinsonian syndromes. These initially diverse diagnoses can progress towards the inclusion of neurological features from each condition.
  • FTD frontotemporal dementia
  • atypical Parkinsonian syndromes These initially diverse diagnoses can progress towards the inclusion of neurological features from each condition.
  • Three distinct mechanisms have been proposed for how the C90RF72 expansion contributes to the development of ALS. First, C90RF72-ALS brains display reduced abundance of C90RF72 transcripts, suggesting that a loss-of-function mechanism may contribute to disease.
  • DPRs dipeptide repeat proteins
  • Distinct transcriptional changes have been identified in C90RF72-ALS/FTD patient brains, including activation of a heat shock factor-1 (HSFl)-associated response.
  • HSFl heat shock factor-1
  • the expression of poly-GR in Drosophila neurons and the treatment of human stem cell-derived neurons with synthetic poly-GR increased levels of HSF1 and HSF1 -associated transcripts. This suggested that DPRs are sufficient to drive disease-associated transcriptional changes and that the effects of DPRs can be modelled in vitro.
  • poly-GR and poly-PR are observed to be toxic to human stem cell-derived NGN2 cortical-like neurons.
  • a high-through put screening platform has been established to identify cellular pathways that modify the toxic effects of DPRs and may provide a venue for therapeutic development in C90RF72-ALS/FTD.

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Abstract

L'invention concerne des composés et des méthodes de traitement de maladies et d'affections liées à des répétitions de dipeptides toxiques comprenant la sclérose latérale amyotrophique (SLA) et la démence fronto-temporale (DFT). L'invention concerne également un procédé de criblage à la recherche d'agents qui traitent ou préviennent des maladies et des affections liées à des répétitions de dipeptides toxiques.
PCT/US2019/063113 2018-11-25 2019-11-25 Composés et méthodes de traitement de maladies neurodégénératives Ceased WO2020107037A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170247471A1 (en) * 2014-09-30 2017-08-31 Neurimmune Holding Ag Human-derived anti-dipeptide repeats (dprs) antibody

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170247471A1 (en) * 2014-09-30 2017-08-31 Neurimmune Holding Ag Human-derived anti-dipeptide repeats (dprs) antibody

Non-Patent Citations (2)

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Title
MCGURK ET AL.: "Nuclear poly(ADP-ribose) Activity Is A Therapeutic Target In Amyotrophic Lateral Sclerosis", ACTA NEUROPATHOLOGICA COMMUNICATIONS, vol. 6, no. 84, 29 August 2018 (2018-08-29), pages 1 - 15, XP021260069, Retrieved from the Internet <URL:https://doi.org/10.1186/s40478-018-0586-1> DOI: 10.1186/s40478-018-0586-1 *
SOLOMON ET AL.: "A feedback loop between dipeptide-repeatprotein, TDP-43 and karyopherin-alpha mediates C9orf72-related neurodegeneration", BRAIN, vol. 141, 25 September 2018 (2018-09-25), pages 2908 - 2924, XP055709675 *

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