IL292148A - Gene therapy for Alzheimer's disease - Google Patents
Gene therapy for Alzheimer's diseaseInfo
- Publication number
- IL292148A IL292148A IL292148A IL29214822A IL292148A IL 292148 A IL292148 A IL 292148A IL 292148 A IL292148 A IL 292148A IL 29214822 A IL29214822 A IL 29214822A IL 292148 A IL292148 A IL 292148A
- Authority
- IL
- Israel
- Prior art keywords
- alzheimer
- disease
- gene therapy
- therapy
- gene
- Prior art date
Links
- 208000024827 Alzheimer disease Diseases 0.000 title 1
- 238000001415 gene therapy Methods 0.000 title 1
Classifications
-
- 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
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
- A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/775—Apolipopeptides
-
- 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
- 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
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/052—Animals comprising random inserted nucleic acids (transgenic) inducing gain of function
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
- A01K2267/0312—Animal model for Alzheimer's disease
-
- 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
- C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
-
- 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
- C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
- C12N2310/141—MicroRNAs, miRNAs
-
- 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
- C12N2310/50—Physical structure
- C12N2310/53—Physical structure partially self-complementary or closed
- C12N2310/531—Stem-loop; Hairpin
-
- 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
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Toxicology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Virology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962915988P | 2019-10-16 | 2019-10-16 | |
| PCT/US2020/056051 WO2021076941A1 (en) | 2019-10-16 | 2020-10-16 | Gene therapy for alzheimer's disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL292148A true IL292148A (en) | 2022-06-01 |
Family
ID=73288693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL292148A IL292148A (en) | 2019-10-16 | 2022-04-11 | Gene therapy for Alzheimer's disease |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US20230405148A1 (https=) |
| EP (1) | EP4045653A1 (https=) |
| JP (2) | JP2023500793A (https=) |
| KR (1) | KR20220082050A (https=) |
| CN (1) | CN114761569A (https=) |
| AU (2) | AU2020367437B2 (https=) |
| BR (1) | BR112022007010A2 (https=) |
| CA (1) | CA3157864A1 (https=) |
| CO (1) | CO2022006367A2 (https=) |
| IL (1) | IL292148A (https=) |
| MX (1) | MX2022004524A (https=) |
| WO (1) | WO2021076941A1 (https=) |
| ZA (1) | ZA202205344B (https=) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7616995B2 (ja) * | 2018-11-28 | 2025-01-17 | プリベイル セラピューティクス，インコーポレーテッド | 神経変性疾患のための遺伝子治療 |
| EP4508213A1 (en) * | 2022-04-12 | 2025-02-19 | uniQure biopharma B.V. | Nucleic acid regulation of apoe |
| EP4551711A1 (en) * | 2022-07-08 | 2025-05-14 | Cornell University | Methods and pharmaceutical compositions for the treatment and the prevention of alzheimers disease |
| WO2025213111A2 (en) * | 2024-04-05 | 2025-10-09 | Cornell University | Aav expression of mirna to suppress human apoe mrna |
Family Cites Families (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4797368A (en) | 1985-03-15 | 1989-01-10 | The United States Of America As Represented By The Department Of Health And Human Services | Adeno-associated virus as eukaryotic expression vector |
| US4863457A (en) | 1986-11-24 | 1989-09-05 | Lee David A | Drug delivery device |
| US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
| AU4198793A (en) | 1992-07-24 | 1994-01-27 | Takeda Chemical Industries Ltd. | Microparticle preparation and production thereof |
| FR2695563B1 (fr) | 1992-09-11 | 1994-12-02 | Pasteur Institut | Microparticules portant des antigènes et leur utilisation pour l'induction de réponses humorales ou cellulaires. |
| ATE163230T1 (de) | 1993-03-09 | 1998-02-15 | Epic Therapeutics Inc | Makromolekulare mikropartikel und verfahren zu ihrer herstellung |
| US6090925A (en) | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
| US5981719A (en) | 1993-03-09 | 1999-11-09 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
| US5603960A (en) | 1993-05-25 | 1997-02-18 | O'hagan; Derek T. | Preparation of microparticles and method of immunization |
| US5464758A (en) | 1993-06-14 | 1995-11-07 | Gossen; Manfred | Tight control of gene expression in eucaryotic cells by tetracycline-responsive promoters |
| US5814618A (en) | 1993-06-14 | 1998-09-29 | Basf Aktiengesellschaft | Methods for regulating gene expression |
| US6913767B1 (en) | 1993-10-25 | 2005-07-05 | Genentech, Inc. | Compositions for microencapsulation of antigens for use as vaccines |
| US5443505A (en) | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
| US6342390B1 (en) | 1994-11-23 | 2002-01-29 | The United States Of America As Represented By The Secretary Of Health And Human Services | Lipid vesicles containing adeno-associated virus rep protein for transgene integration and gene therapy |
| CA2267930A1 (en) | 1996-10-09 | 1998-04-16 | Nobuyuki Takechi | A method for producing a microparticle |
| US6210707B1 (en) | 1996-11-12 | 2001-04-03 | The Regents Of The University Of California | Methods of forming protein-linked lipidic microparticles, and compositions thereof |
| US6884435B1 (en) | 1997-01-30 | 2005-04-26 | Chiron Corporation | Microparticles with adsorbent surfaces, methods of making same, and uses thereof |
| GB9810236D0 (en) | 1998-05-13 | 1998-07-08 | Microbiological Res Authority | Improvements relating to encapsulation of bioactive agents |
| US6406719B1 (en) | 1998-05-13 | 2002-06-18 | Microbiological Research Authority | Encapsulation of bioactive agents |
| US6264987B1 (en) | 2000-05-19 | 2001-07-24 | Alkermes Controlled Therapeutics Inc. Ii | Method for preparing microparticles having a selected polymer molecular weight |
| FR2814642B1 (fr) | 2000-10-03 | 2005-07-01 | Ass Pour Le Dev De La Rech En | Souris transgenique pour la recombinaison ciblee mediee par la cre-er modifiee |
| US6723551B2 (en) | 2001-11-09 | 2004-04-20 | The United States Of America As Represented By The Department Of Health And Human Services | Production of adeno-associated virus in insect cells |
| EP1752536A4 (en) * | 2004-05-11 | 2008-04-16 | Alphagen Co Ltd | POLYNUCLEOTIDE CAUSING RNA INTERFERENCE AND METHOD OF REGULATING GENE EXPRESSION WITH THE USE OF THE SAME |
| WO2007041190A2 (en) | 2005-09-30 | 2007-04-12 | The University Of Iowa Research Foundation | Polymer-based delivery system for immunotherapy of cancer |
| CA2643048A1 (en) * | 2006-02-21 | 2007-08-30 | Oklahoma Medical Research Foundation | Treatment of alzheimer's disease with inhibitors of apoe binding to apoe receptor |
| KR20140102327A (ko) * | 2007-02-06 | 2014-08-21 | 유태준 | 유전자 요법을 사용한 신경퇴행성 질환의 치료 및 예방 |
| US9572894B2 (en) | 2010-10-18 | 2017-02-21 | The University Of Iowa Research Foundation | Biodegradable particulate formulations |
| WO2012115806A1 (en) | 2011-02-24 | 2012-08-30 | University Of Iowa Research Foundation | New biodegradable polymers with sulfenamide bonds for drug delivery applications |
| JP6469000B2 (ja) * | 2012-05-18 | 2019-02-13 | ユニバーシティー オブ アイオワ リサーチ ファウンデーション | アミロイドの沈着を処置するための方法および組成物 |
| WO2013181618A2 (en) * | 2012-05-31 | 2013-12-05 | The Trustees Of Columbia University In The City Of New York | Methods to treat alzheimer's disease using apoe inhibitors |
| MX2016006584A (es) * | 2013-11-20 | 2016-09-06 | Univ Iowa Res Found | Métodos y composiciones para tratar los depósitos de amiloide. |
| WO2018045347A1 (en) * | 2016-09-02 | 2018-03-08 | Spark Therapeutics, Inc. | Methods and vectors for treating cns disorders |
| US11071791B2 (en) * | 2018-01-26 | 2021-07-27 | Wisconsin Alumni Research Foundation | Vector for gene silencing and replacement and methods of use thereof |
| JP7616995B2 (ja) * | 2018-11-28 | 2025-01-17 | プリベイル セラピューティクス，インコーポレーテッド | 神経変性疾患のための遺伝子治療 |
-
2020
- 2020-10-16 EP EP20804387.7A patent/EP4045653A1/en active Pending
- 2020-10-16 BR BR112022007010A patent/BR112022007010A2/pt unknown
- 2020-10-16 KR KR1020227016247A patent/KR20220082050A/ko active Pending
- 2020-10-16 US US17/769,255 patent/US20230405148A1/en active Pending
- 2020-10-16 WO PCT/US2020/056051 patent/WO2021076941A1/en not_active Ceased
- 2020-10-16 JP JP2022522814A patent/JP2023500793A/ja active Pending
- 2020-10-16 CN CN202080073402.8A patent/CN114761569A/zh active Pending
- 2020-10-16 AU AU2020367437A patent/AU2020367437B2/en active Active
- 2020-10-16 CA CA3157864A patent/CA3157864A1/en active Pending
- 2020-10-16 MX MX2022004524A patent/MX2022004524A/es unknown
-
2022
- 2022-04-11 IL IL292148A patent/IL292148A/en unknown
- 2022-05-13 ZA ZA2022/05344A patent/ZA202205344B/en unknown
- 2022-05-16 CO CONC2022/0006367A patent/CO2022006367A2/es unknown
-
2025
- 2025-02-06 AU AU2025200812A patent/AU2025200812A1/en active Pending
- 2025-12-05 JP JP2025233417A patent/JP2026041903A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US20230405148A1 (en) | 2023-12-21 |
| CA3157864A1 (en) | 2021-04-22 |
| JP2026041903A (ja) | 2026-03-10 |
| JP2023500793A (ja) | 2023-01-11 |
| WO2021076941A1 (en) | 2021-04-22 |
| ZA202205344B (en) | 2023-03-29 |
| AU2020367437B2 (en) | 2024-11-07 |
| BR112022007010A2 (pt) | 2022-07-12 |
| AU2025200812A1 (en) | 2025-02-27 |
| MX2022004524A (es) | 2022-07-21 |
| EP4045653A1 (en) | 2022-08-24 |
| WO2021076941A9 (en) | 2021-10-07 |
| KR20220082050A (ko) | 2022-06-16 |
| AU2020367437A1 (en) | 2022-06-02 |
| CO2022006367A2 (es) | 2022-08-09 |
| CN114761569A (zh) | 2022-07-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| IL278813A (en) | Gene therapy for Alzheimer's disease | |
| PT3873604T (pt) | Métodos para tratar a doença de alzheimer com hp-[beta]-ciclodextrina | |
| ZA202205344B (en) | Gene therapy for alzheimer's disease | |
| IL288266A (en) | Gene therapy for Alzheimer's disease | |
| EP3292206B8 (en) | Glucocerebrosidase gene therapy for parkinson's disease | |
| IL285238A (en) | Gene therapy vectors for treatment of danon disease | |
| IL263188B (en) | Treatment for Parkinson's disease | |
| IL280326A (en) | Small RNA contracts for Alzheimer's disease | |
| GB201522416D0 (en) | Wilson's disease gene therapy | |
| PL4284387T3 (pl) | Terapia podnosząca poziom NAD w chorobie Parkinsona | |
| GB201915753D0 (en) | Alzheimer's disease | |
| ZA202006126B (en) | Compounds for treating alzheimer's disease | |
| IL276701A (en) | Oligonucleotide therapy for Wilson's disease | |
| GB201817469D0 (en) | Gene therapy for retinal disease | |
| HK40070171A (en) | Gene therapy for alzheimer's disease | |
| HK40050811A (en) | Gene therapy for alzheimer's disease | |
| EP3244897A4 (en) | Methods for treating alzheimer's disease | |
| GB201911728D0 (en) | Bacterial composistions for the treatment of disease | |
| GB202200884D0 (en) | NAD-augmentation therapy for Parkinson's disease | |
| AU2018903530A0 (en) | Treatment for Alzheimer's Disease | |
| GB201819758D0 (en) | Medicine for the treatment of Alzheimer's disease | |
| HK40082515A (en) | Compounds for treatment of alzheimer's disease | |
| HK40041162A (en) | Compounds for treating alzheimer's disease | |
| HK40079761A (en) | Anti-beta-amyloid antibody for treating alzheimer's disease | |
| HK40079762A (en) | Methods for treating parkinson's disease |