WO2019213245A1 - Methods for reducing accumulated pathologic tau protein - Google Patents

Methods for reducing accumulated pathologic tau protein Download PDF

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Publication number
WO2019213245A1
WO2019213245A1 PCT/US2019/030184 US2019030184W WO2019213245A1 WO 2019213245 A1 WO2019213245 A1 WO 2019213245A1 US 2019030184 W US2019030184 W US 2019030184W WO 2019213245 A1 WO2019213245 A1 WO 2019213245A1
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WO
WIPO (PCT)
Prior art keywords
months
accumulated
dspbn
subject
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2019/030184
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English (en)
French (fr)
Inventor
Richard D. Kopke
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Hough Ear Institute
Original Assignee
Hough Ear Institute
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Filing date
Publication date
Application filed by Hough Ear Institute filed Critical Hough Ear Institute
Priority to JP2020561795A priority Critical patent/JP2021523126A/ja
Priority to EP19723991.6A priority patent/EP3787750A1/en
Priority to US17/052,093 priority patent/US20210137861A1/en
Publication of WO2019213245A1 publication Critical patent/WO2019213245A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the accumulated pathologic Tau protein is caused by a central nervous system disease.
  • the 2,4-DSPBN or pharmaceutically acceptable salt thereof is administered to the subject at least two months, at least three months, at least six months, at least nine months, at least twelve months, or 1-60 months after onset of the central nervous system disease.
  • cerebrospinal fluid of the subject comprises at least 0.05 ng/ml, or at least 0.07 ng/ml, or at least 0.1 ng/ml, or at least 0.15 ng/ml, or at least 0.2 ng/ml, or at least 0.25 ng/ml, or at least 0.3 ng/ml, or at least 0.35 ng/ml, or at least 0.4 ng/ml, or at least 0.45 ng/ml, or at least 0.5 ng/ml, of accumulated pathologic Tau protein.
  • Figure 1 shows T22 positive neuron counting and statistical analyses in the spiral ganglion (SG) after noise exposure. Rats were exposed to 115 dB SPL octave band noise for one hour. One group of rats were treated with 2,4-DSPBN and NAC (300 mg/kg of each) one hour after noise exposure and twice /day for the next two days (total 5 doses, the N/T group) while another group of rats were treated with vehicle (saline) only (the N group). One group of rats without noise exposure served as normal controls (the NC group). Animals were euthanized at 7- and 21 -days after noise exposure, and cochlear tissues were processed for immunostaining.
  • 2,4-disulfonyl a-phenyl tertiary butyl nitrone is also referred to as 2,4-disulfonyl PBN, 2,4-DSPBN, NXY-059, HPN-07, or CAS 168021-79-2. It has the following structure:
  • 2,4-DSPBN is described in detail by U.S. Pat. No. 5,488,145, which is incorporated herein by reference.
  • the salts of 2,4-DSPBN may also be used for reducing accumulated pathologic Tau protein in a manner similar to the use of 2,4- DSPBN as described herein.
  • the nitrone compound is selected from phenyl butyl nitrone (PBN) and its derivatives. In some embodiments, the nitrone compound is PBN. In some embodiments, the nitrone compound is 4-hydroxy-a-phenyl butyl nitrone (4-OHPBN). In some embodiments, the nitrone compound is 2-sulfonyl-a-phenyl tertiary butyl nitrone (S-PBN).
  • PBN phenyl butyl nitrone
  • S-PBN 2-sulfonyl-a-phenyl tertiary butyl nitrone
  • the method further comprises administering a Tau aggregation inhibitor.
  • the Tau aggregation inhibitor can be a covalent or non-covalent inhibitor.
  • Non-limiting examples of Tau aggregation inhibitors include curcumin, molecular tweezers (e.g., CLR01), phthalocyanine tetrasulfonate, oleocanthal, cinnamaldehyde, baicalein, isoprenaline, dopamine, dobutamine, levodopa, levodopa/carbidopa, trimetoquinol, hexoprenaline, methyldopa, and droxidopa.
  • an effective amount of 2,4-DSPBN or its pharmaceutically acceptable salt and optionally NAC are administered to a human patient suffering from CTE, wherein the 2,4-DSPBN or its pharmaceutically acceptable salt and the optional NAC reduce the amount of accumulated pathologic Tau proteins in the central nervous system to a level sufficient to deliver a therapeutic benefit to the patient against CTE.
  • a further aspect of the invention relates to a method for reducing accumulated pathologic Tau protein in a patient suffering from progressive supranuclear palsy (PSP).
  • cerebrospinal fluid of the patient contains at least 0.05 ng/ml, or at least 0.07 ng/ml, or at least 0.1 ng/ml, or at least 0.15 ng/ml, or at least 0.2 ng/ml, or at least 0.25 ng/ml, or at least 0.3 ng/ml, or at least 0.35 ng/ml, or at least 0.4 ng/ml, or at least 0.45 ng/ml, or at least 0.5 ng/ml, of accumulated pathologic Tau protein.
  • an effective amount of 2,4-DSPBN or its pharmaceutically acceptable salt and optionally NAC are administered to a human patient suffering from FTD, wherein the 2,4-DSPBN or its pharmaceutically acceptable salt and the optional NAC reduce the amount of accumulated pathologic Tau proteins in the central nervous system to a level sufficient to deliver a therapeutic benefit to the patient against FTD.
  • an effective amount of 2,4-DSPBN or its pharmaceutically acceptable salt and optionally NAC are administered to a human patient suffering from HSD, wherein the 2,4-DSPBN or its pharmaceutically acceptable salt and the optional NAC reduce the amount of accumulated pathologic Tau proteins in the central nervous system to a level sufficient to deliver a therapeutic benefit to the patient against HSD.
  • a further aspect of the invention relates to a method for reducing accumulated pathologic Tau protein in a patient suffering from multiple system atrophy (MSA).
  • cerebrospinal fluid of the patient contains at least 0.05 ng/ml, or at least 0.07 ng/ml, or at least 0.1 ng/ml, or at least 0.15 ng/ml, or at least 0.2 ng/ml, or at least 0.25 ng/ml, or at least 0.3 ng/ml, or at least 0.35 ng/ml, or at least 0.4 ng/ml, or at least 0.45 ng/ml, or at least 0.5 ng/ml, of accumulated pathologic Tau protein.
  • an effective amount of 2,4-DSPBN or its pharmaceutically acceptable salt and optionally NAC are administered to a human patient suffering from NPC, wherein the 2,4-DSPBN or its pharmaceutically acceptable salt and the optional NAC reduce the amount of accumulated pathologic Tau proteins in the central nervous system to a level sufficient to deliver a therapeutic benefit to the patient against NPC.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/US2019/030184 2018-05-03 2019-05-01 Methods for reducing accumulated pathologic tau protein Ceased WO2019213245A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2020561795A JP2021523126A (ja) 2018-05-03 2019-05-01 蓄積した病理学的Ｔａｕタンパク質を低減する方法
EP19723991.6A EP3787750A1 (en) 2018-05-03 2019-05-01 Methods for reducing accumulated pathologic tau protein
US17/052,093 US20210137861A1 (en) 2018-05-03 2019-05-01 Methods for reducing accumulated pathologic tau protein

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862666459P 2018-05-03 2018-05-03
US62/666,459 2018-05-03

Publications (1)

Publication Number Publication Date
WO2019213245A1 true WO2019213245A1 (en) 2019-11-07

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PCT/US2019/030184 Ceased WO2019213245A1 (en) 2018-05-03 2019-05-01 Methods for reducing accumulated pathologic tau protein

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US (1) US20210137861A1 (https=)
EP (1) EP3787750A1 (https=)
JP (1) JP2021523126A (https=)
WO (1) WO2019213245A1 (https=)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230092005A1 (en) * 2020-02-24 2023-03-23 Oblato, Inc. Compositions and methods for treating cancer and tumor

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021522282A (ja) 2018-04-27 2021-08-30 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニアＴｈｅ Ｒｅｇｅｎｔｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｃａｌｉｆｏｒｎｉａ リソソーム蓄積障害の治療
US12076330B2 (en) 2018-04-27 2024-09-03 The Regents Of The University Of California Inhibition of lipofuscin aggregation by molecular tweezers

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5488145A (en) 1993-12-23 1996-01-30 Oklahoma Medical Research Foundation 2,4-disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceutical free radical traps
WO2011028503A1 (en) * 2009-08-24 2011-03-10 Hough Ear Institute Methods for treating acute acoustic trauma
WO2012106654A1 (en) * 2011-02-04 2012-08-09 Hough Ear Institute Methods for treating brain injury
WO2017048778A1 (en) * 2015-09-18 2017-03-23 Oklahoma Medical Research Foundation Method of transporting an agent across blood-brain, blood-cochlear or blood-cerebrospinal fluid barrier

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2270421T3 (es) * 1993-12-21 2007-04-01 Innogenetics N.V. Anticuerpos monoclonales especificos para phf-tau, hibridomas que secretan los mismos, reconocimiento de antigeno por estos anticuerpos y sus aplicaciones.
AU2003291358A1 (en) * 2002-11-07 2004-06-03 Molecular Geriatrics Corporation Methods for predicting whether subjects with mild cognitive impairment (mci) will develop alzheimer's disease
EP2764863B1 (en) * 2011-10-03 2020-03-11 National Center for Geriatrics and Gerontology Tau aggregation inhibitor
US10576125B2 (en) * 2016-10-31 2020-03-03 Hough Ear Institute Methods for enhancing synaptogenesis and neuritogenesis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5488145A (en) 1993-12-23 1996-01-30 Oklahoma Medical Research Foundation 2,4-disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceutical free radical traps
WO2011028503A1 (en) * 2009-08-24 2011-03-10 Hough Ear Institute Methods for treating acute acoustic trauma
WO2012106654A1 (en) * 2011-02-04 2012-08-09 Hough Ear Institute Methods for treating brain injury
WO2017048778A1 (en) * 2015-09-18 2017-03-23 Oklahoma Medical Research Foundation Method of transporting an agent across blood-brain, blood-cochlear or blood-cerebrospinal fluid barrier

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BERGER ET AL., J NEUROSCI., vol. 27, no. 14, 2007, pages 3650 - 62
BERGER ET AL., NEUROSCI., vol. 27, no. 14, 2007, pages 3650 - 62
BOBAN ET AL., J NEUROSCI METHODS., vol. S0165-0270, no. 18, 2018, pages 30297 - 8

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230092005A1 (en) * 2020-02-24 2023-03-23 Oblato, Inc. Compositions and methods for treating cancer and tumor

Also Published As

Publication number Publication date
EP3787750A1 (en) 2021-03-10
US20210137861A1 (en) 2021-05-13
JP2021523126A (ja) 2021-09-02

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