EA201892431A1 - Олигонуклеотиды для лечения заболевания глаз - Google Patents

Олигонуклеотиды для лечения заболевания глаз

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Publication number
EA201892431A1
EA201892431A1 EA201892431A EA201892431A EA201892431A1 EA 201892431 A1 EA201892431 A1 EA 201892431A1 EA 201892431 A EA201892431 A EA 201892431A EA 201892431 A EA201892431 A EA 201892431A EA 201892431 A1 EA201892431 A1 EA 201892431A1
Authority
EA
Eurasian Patent Office
Prior art keywords
oligonucleotides
treatment
eye diseases
ush2a
exon
Prior art date
Application number
EA201892431A
Other languages
English (en)
Russian (ru)
Inventor
Хестер Катарина Ван Дипен
Хэ Ламь Чань
Джанне Джуха Турунен
Original Assignee
ПРОКЬЮЭР ТЕРАПЬЮТИКС II Би.Ви.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ПРОКЬЮЭР ТЕРАПЬЮТИКС II Би.Ви. filed Critical ПРОКЬЮЭР ТЕРАПЬЮТИКС II Би.Ви.
Publication of EA201892431A1 publication Critical patent/EA201892431A1/ru

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • A61K31/7125Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088Compounds having three or more nucleosides or nucleotides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
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    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111General methods applicable to biologically active non-coding nucleic acids
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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113Non-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
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/10Type of nucleic acid
    • C12N2310/11Antisense
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/31Chemical structure of the backbone
    • C12N2310/315Phosphorothioates
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/32Chemical structure of the sugar
    • C12N2310/3212'-O-R Modification
    • CCHEMISTRY; METALLURGY
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/33Chemical structure of the base
    • C12N2310/333Modified A
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/33Chemical structure of the base
    • C12N2310/334Modified C
    • C12N2310/33415-Methylcytosine
    • CCHEMISTRY; METALLURGY
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    • C12N2310/00Structure or type of the nucleic acid
    • C12N2310/30Chemical structure
    • C12N2310/35Nature of the modification
    • C12N2310/352Nature of the modification linked to the nucleic acid via a carbon atom
    • C12N2310/3521Methyl
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00Applications; Uses
    • C12N2320/30Special therapeutic applications
    • C12N2320/33Alteration of splicing

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EA201892431A 2016-04-25 2017-04-25 Олигонуклеотиды для лечения заболевания глаз EA201892431A1 (ru)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB201607141 2016-04-25
PCT/EP2017/059830 WO2017186739A1 (en) 2016-04-25 2017-04-25 Oligonucleotides to treat eye disease

Publications (1)

Publication Number Publication Date
EA201892431A1 true EA201892431A1 (ru) 2019-04-30

Family

ID=58672573

Family Applications (1)

Application Number Title Priority Date Filing Date
EA201892431A EA201892431A1 (ru) 2016-04-25 2017-04-25 Олигонуклеотиды для лечения заболевания глаз

Country Status (15)

Country Link
US (3) US10617707B2 (OSRAM)
EP (1) EP3448999B1 (OSRAM)
JP (1) JP7043082B2 (OSRAM)
KR (1) KR102368920B1 (OSRAM)
CN (1) CN109072239A (OSRAM)
AU (1) AU2017257292A1 (OSRAM)
CA (1) CA3021899A1 (OSRAM)
DK (1) DK3448999T3 (OSRAM)
EA (1) EA201892431A1 (OSRAM)
ES (1) ES2801823T3 (OSRAM)
IL (1) IL262199B (OSRAM)
MX (1) MX2018013003A (OSRAM)
PL (1) PL3448999T3 (OSRAM)
WO (1) WO2017186739A1 (OSRAM)
ZA (1) ZA201806628B (OSRAM)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2801823T3 (es) 2016-04-25 2021-01-14 Proqr Therapeutics Ii Bv Oligonucleótidos para tratar una enfermedad ocular
CN109477103A (zh) 2016-06-22 2019-03-15 ProQR治疗上市公司Ⅱ 单链rna-编辑寡核苷酸
NZ751483A (en) 2016-09-01 2022-07-01 Proqr Therapeutics Ii Bv Chemically modified single-stranded rna-editing oligonucleotides
GB201706009D0 (en) 2017-04-13 2017-05-31 Proqr Therapeutics Ii Bv Antisense oligonucleotides for the treatment of stargardt disease
CA3084633A1 (en) 2017-12-21 2019-06-27 Crispr Therapeutics Ag Materials and methods for treatment of usher syndrome type 2a and/or non-syndromic autosomal recessive retinitis pigmentosa (arrp)
AU2018393050A1 (en) 2017-12-21 2020-06-18 Bayer Healthcare Llc Materials and methods for treatment of Usher Syndrome Type 2A
GB201808146D0 (en) 2018-05-18 2018-07-11 Proqr Therapeutics Ii Bv Stereospecific Linkages in RNA Editing Oligonucleotides
CA3124493A1 (en) 2019-01-28 2020-08-06 Proqr Therapeutics Ii B.V. Rna-editing oligonucleotides for the treatment of usher syndrome
CA3127527A1 (en) * 2019-02-12 2020-08-20 Universita Degli Studi Di Trento Cas12a guide rna molecules and uses thereof
US20220177894A1 (en) 2019-04-02 2022-06-09 Proqr Therapeutics Ii B.V. Antisense oligonucleotides for immunotherapy
CR20210572A (es) 2019-04-15 2022-04-07 Univ Beijing Métodos y composiciones para editar ácido ribonucleicos (arn)
AU2020259856A1 (en) 2019-04-18 2021-11-18 Proqr Therapeutics Ii B.V. Antisense oligonucleotides for the treatment of usher syndrome
WO2020254249A1 (en) 2019-06-21 2020-12-24 Proqr Therapeutics Ii B.V. Delivery of nucleic acids for the treatment of auditory disorders
MX2022000497A (es) 2019-07-12 2022-02-03 Univ Beijing Edicion de acido ribonucleico (arn) dirigido aprovechando la adenosina desaminasa que actua sobre acido ribonucleico endogeno (adar) utilizando acidos ribonucleicos (arn) modificados geneticamente.
US20220265695A1 (en) 2019-07-26 2022-08-25 Proqr Therapeutics Ii B.V. Opthalmic compositions comprising viscosifying polymers and nucleic acids
EP4010475A1 (en) * 2019-08-08 2022-06-15 UCL Business Ltd Antisense oligonucleotides rescue aberrant splicing of abca4
WO2021130313A1 (en) 2019-12-23 2021-07-01 Proqr Therapeutics Ii B.V. Antisense oligonucleotides for nucleotide deamination in the treatment of stargardt disease
IL294260A (en) * 2019-12-30 2022-08-01 Edigene Therapeutics Beijing Inc Method for treating usher syndrome and composition thereof
CN113122577A (zh) * 2019-12-30 2021-07-16 博雅辑因(北京)生物科技有限公司 一种治疗Usher综合征的方法和其组合物
WO2021175904A1 (en) 2020-03-04 2021-09-10 Proqr Therapeutics Ii B.V. Antisense oligonucleotides for use in the treatment of usher syndrome
WO2022184888A2 (en) 2021-03-05 2022-09-09 Proqr Therapeutics Ii B.V. Antisense oligonucleotides for use in the treatment of corneal dystrophies
TR2022001648A2 (tr) * 2022-02-09 2022-02-21 T C Ueskuedar Ueniversitesi Ush2a kaynaklı retinitis pigmentosa hastalığının genetik tedavisi için ekzon 13 atlama işlevi gören kseno nükleik asit antisens-oligonükleotit (xna-aso) dizileri.
EP4479535A1 (en) 2022-02-14 2024-12-25 ProQR Therapeutics II B.V. Guide oligonucleotides for nucleic acid editing in the treatment of hypercholesterolemia
EP4599061A1 (en) * 2022-10-06 2025-08-13 Stichting Radboud universitair medisch centrum Antisense oligonucleotides for treatment of usher 2a. exon 68
WO2024074668A1 (en) * 2022-10-06 2024-04-11 Stichting Radboud Universitair Medisch Centrum Antisense oligonucleotides for treatment of usher 2a. exons 30-31
CN120129747A (zh) * 2022-10-11 2025-06-10 广州瑞风生物科技有限公司 snRNA核酸分子及其应用
WO2024105063A1 (en) * 2022-11-15 2024-05-23 Stichting Radboud Universitair Medisch Centrum Antisense oligonucleotides for treatment of usher 2a. exons 39-40
WO2025007937A1 (zh) * 2023-07-04 2025-01-09 广州瑞风生物科技有限公司 靶向USH2A pre-mRNA假外显子PE40的snRNA及其应用

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6503713B1 (en) 1999-10-04 2003-01-07 University Of Medicine And Dentistry Of New Jersey Methods for identifying RNA binding compounds
EP1191097A1 (en) 2000-09-21 2002-03-27 Leids Universitair Medisch Centrum Induction of exon skipping in eukaryotic cells
US20100196889A1 (en) 2006-11-13 2010-08-05 Bankaitis-Davis Danute M Gene Expression Profiling for Identification, Monitoring and Treatment of Colorectal Cancer
US8093000B2 (en) 2008-05-09 2012-01-10 The Regents Of The University Of California Methods for predicting and treating tumors resistant to drug, immunotherapy, and radiation
US20110070582A1 (en) 2008-11-03 2011-03-24 Source Precision Medicine, Inc. d/b/d Source MDX Gene Expression Profiling for Predicting the Response to Immunotherapy and/or the Survivability of Melanoma Subjects
SI2425814T1 (sl) 2010-09-03 2013-10-30 Novagali Pharma S.A. Emulzija vrste voda-v-olju za zdravljenje bolezni očesa
CA2952289C (en) * 2014-07-10 2024-07-02 Stichting Radboud Universitair Medisch Centrum Antisense oligonucleotides for the treatment of type 2 Usher syndrome
US9927034B2 (en) 2015-08-25 2018-03-27 Mueller International, Llc Valve seat stiffener
EP3359667A1 (en) 2015-10-05 2018-08-15 ProQR Therapeutics II B.V. Use of single-stranded antisense oligonucleotide in prevention or treatment of genetic diseases involving a trinucleotide repeat expansion
ES2801823T3 (es) 2016-04-25 2021-01-14 Proqr Therapeutics Ii Bv Oligonucleótidos para tratar una enfermedad ocular

Also Published As

Publication number Publication date
KR102368920B1 (ko) 2022-02-28
US20200237802A1 (en) 2020-07-30
CA3021899A1 (en) 2017-11-02
US20190381089A1 (en) 2019-12-19
JP2019515688A (ja) 2019-06-13
ES2801823T3 (es) 2021-01-14
DK3448999T3 (da) 2020-06-08
AU2017257292A1 (en) 2018-12-06
IL262199B (en) 2022-03-01
CN109072239A (zh) 2018-12-21
MX2018013003A (es) 2019-01-28
IL262199A (en) 2018-12-31
KR20180134931A (ko) 2018-12-19
US11123360B2 (en) 2021-09-21
JP7043082B2 (ja) 2022-03-29
US20210401871A1 (en) 2021-12-30
EP3448999B1 (en) 2020-05-13
EP3448999A1 (en) 2019-03-06
US10617707B2 (en) 2020-04-14
PL3448999T3 (pl) 2020-11-30
WO2017186739A1 (en) 2017-11-02
ZA201806628B (en) 2019-07-31

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