CN111183234A - 在表达pnpla3 i148m变异的患者的肝病治疗中对hsd17b13的抑制 - Google Patents

在表达pnpla3 i148m变异的患者的肝病治疗中对hsd17b13的抑制 Download PDF

Info

Publication number
CN111183234A
CN111183234A CN201880065116.XA CN201880065116A CN111183234A CN 111183234 A CN111183234 A CN 111183234A CN 201880065116 A CN201880065116 A CN 201880065116A CN 111183234 A CN111183234 A CN 111183234A
Authority
CN
China
Prior art keywords
seq
protein
hsd17b13
nucleic acid
encoding
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.)
Pending
Application number
CN201880065116.XA
Other languages
English (en)
Chinese (zh)
Inventor
辛玉蓉
J·格罗马达
程希平
F·杜威
T·特斯洛维奇·多斯塔尔
C·舒尔曼
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=64316974&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN111183234(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of CN111183234A publication Critical patent/CN111183234A/zh
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • C12N15/1137—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 against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • C12N2310/50—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
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Plant Pathology (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Virology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
CN201880065116.XA 2017-10-11 2018-10-11 在表达pnpla3 i148m变异的患者的肝病治疗中对hsd17b13的抑制 Pending CN111183234A (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201762570985P 2017-10-11 2017-10-11
US62/570,985 2017-10-11
PCT/US2018/055377 WO2019075181A1 (en) 2017-10-11 2018-10-11 INHIBITION OF HSD17B13 IN THE TREATMENT OF HEPATIC DISEASE IN PATIENTS EXPRESSING PNPLA3 I148M VARIATION

Publications (1)

Publication Number Publication Date
CN111183234A true CN111183234A (zh) 2020-05-19

Family

ID=64316974

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201880065116.XA Pending CN111183234A (zh) 2017-10-11 2018-10-11 在表达pnpla3 i148m变异的患者的肝病治疗中对hsd17b13的抑制

Country Status (13)

Country Link
US (4) US10961583B2 (https=)
EP (3) EP4685243A3 (https=)
JP (3) JP7434151B2 (https=)
KR (2) KR102694809B1 (https=)
CN (1) CN111183234A (https=)
AU (2) AU2018348195B2 (https=)
CA (1) CA3078883A1 (https=)
IL (2) IL273550B2 (https=)
MX (1) MX2020003561A (https=)
NZ (1) NZ763161A (https=)
RU (1) RU2020115526A (https=)
SG (1) SG11202003254SA (https=)
WO (1) WO2019075181A1 (https=)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112626199A (zh) * 2021-01-04 2021-04-09 杭州艾迪康医学检验中心有限公司 检测慢性肝炎转化为肝硬化的风险预测位点的引物和方法
CN118813778A (zh) * 2024-07-01 2024-10-22 北京泛生子基因科技有限公司 一种试剂盒、使用方法及存储介质

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
RU2019126483A (ru) 2017-01-23 2021-02-24 Ридженерон Фармасьютикалз, Инк. Варианты 17-бета-гидроксистероиддегидрогеназы 13 (hsd17b13) и их применение
AU2018348195B2 (en) * 2017-10-11 2025-05-15 Regeneron Pharmaceuticals, Inc. Inhibition of HSD17B13 in the treatment of liver disease in patients expressing the PNPLA3 I148M variation
AU2019239971B2 (en) 2018-03-21 2025-09-11 Regeneron Pharmaceuticals, Inc. 17beta-hydroxysteroid dehydrogenase type 13 (HSD17b13) iRNA compositions and methods of use thereof
KR102769565B1 (ko) 2018-09-19 2025-02-20 애로우헤드 파마슈티컬스 인코포레이티드 17베타-HSD 유형 13- (HSD17B13)의 발현을 억제하기 위한 RNAi 작용제, 그의 조성물, 및 사용 방법
CR20210395A (es) * 2018-12-21 2021-11-05 Ionis Pharmaceuticals Inc Moduladores de la expresión de hsd17b13
US11957687B2 (en) 2019-07-02 2024-04-16 Regeneron Pharmaceuticals, Inc. Modulators of HSD17B13 and methods of use thereof
WO2021211981A1 (en) * 2020-04-18 2021-10-21 Inipharm, Inc. Substrate selective hsd17b13 inhibitors and uses thereof
WO2021211959A2 (en) * 2020-04-18 2021-10-21 Inipharm, Inc. Methods and compositions for treating drug induced steatohepatitis
JP7626423B6 (ja) 2020-10-16 2025-03-03 公立大学法人大阪 線維症治療薬
MX2023007587A (es) * 2020-12-23 2023-09-21 Regeneron Pharma Tratamiento de enfermedades hepaticas con inhibidores de efectores b tipo dffa que inducen la muerte celular (cideb).
CN118103038A (zh) 2021-08-20 2024-05-28 英安塔制药有限公司 17β-羟基类固醇脱氢酶13型抑制剂及其使用方法
US20230193392A1 (en) 2021-12-20 2023-06-22 Regeneron Pharmaceuticals, Inc. Methods Of Identifying And Evaluating Liver Inflammation And Liver Fibrosis In A Subject By Determining A Stratified Score Based On Gene Expression
CN114262738B (zh) * 2021-12-31 2023-03-31 吉林大学第一医院 Hsd17b13基因多态性在中重度mafld诊断中的应用
TW202400791A (zh) * 2022-05-06 2024-01-01 大陸商蘇州瑞博生物技術股份有限公司 一種核酸、含有該核酸的組合物與綴合物及製備方法和用途
KR20250075705A (ko) * 2022-10-07 2025-05-28 화이자 인코포레이티드 Hsd17b13 억제제 및/또는 분해제
WO2024173343A1 (en) 2023-02-14 2024-08-22 Regeneron Pharmaceuticals, Inc. Compounds targeting hydroxysteroid 17-beta dehydrogenase (hsd17b) and uses thereof
WO2025012422A1 (en) 2023-07-13 2025-01-16 Enyo Pharma L-arginine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof
WO2025012425A1 (en) 2023-07-13 2025-01-16 Enyo Pharma Tromethamine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof
WO2025012038A1 (en) 2023-07-13 2025-01-16 Enyo Pharma L-lysine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof
WO2025098440A1 (zh) * 2023-11-08 2025-05-15 浙江扬厉医药技术有限公司 抑制PNPLA3表达的双链siRNA以及其缀合物
WO2026002833A1 (en) 2024-06-24 2026-01-02 Enyo Pharma Ethanolamine salt of 4-chloro-5-[4-(2,6-dichlorophenyl)sulfonylpiperazin-1-yl]-1-benzofuran-2-carboxylic acid and various forms thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103520724A (zh) * 2013-10-23 2014-01-22 北京美森生物医药科技有限公司 Hsd17b13蛋白或其编码基因的抑制剂的新用途
WO2017048620A1 (en) * 2015-09-14 2017-03-23 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting patatin-like phospholipase domain containing 3 (pnpla3) and methods of use thereof

Family Cites Families (133)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US38170A (en) 1863-04-14 Improvement in lamps
US5294533A (en) 1988-07-05 1994-03-15 Baylor College Of Medicine Antisense oligonucleotide antibiotics complementary to the macromolecular synthesis operon, methods of treating bacterial infections and methods for identification of bacteria
US5135917A (en) 1990-07-12 1992-08-04 Nova Pharmaceutical Corporation Interleukin receptor expression inhibiting antisense oligonucleotides
US5271941A (en) 1990-11-02 1993-12-21 Cho Chung Yoon S Antisense oligonucleotides of human regulatory subunit RI.sub.α of cAMP-dependent protein kinases
US5786138A (en) 1993-01-29 1998-07-28 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Hyperstabilizing antisense nucleic acid binding agents
CA2164288A1 (en) 1993-06-04 1994-12-22 Barbara Ensoli Method for treating kaposi's sarcoma with antisense oligonucleotides
US5578716A (en) 1993-12-01 1996-11-26 Mcgill University DNA methyltransferase antisense oligonucleotides
US5641754A (en) 1994-01-10 1997-06-24 The Board Of Regents Of The University Of Nebraska Antisense oligonucleotide compositions for selectively killing cancer cells
US5624813A (en) 1994-04-21 1997-04-29 Mahant; Vijay K. NAD(P)+ /NAD(P)H based chemiluminescent diagnostics
EP0775204A1 (en) 1994-08-09 1997-05-28 Novartis AG Antitumor antisense oligonucleotides
US5856103A (en) 1994-10-07 1999-01-05 Board Of Regents The University Of Texas Method for selectively ranking sequences for antisense targeting
US5994320A (en) 1995-02-06 1999-11-30 Regents Of The University Of Minnesota Antisense oligonucleotides and methods for treating central nervous system tumors
IT1275862B1 (it) 1995-03-03 1997-10-24 Consiglio Nazionale Ricerche Trascritto antisenso associato ad alcuni tipi di cellule tumorali ed oligodeossinucleotidi sintetici utili nella diagnosi e nel trattamento
US6040296A (en) 1995-06-07 2000-03-21 East Carolina University Specific antisense oligonucleotide composition & method for treatment of disorders associated with bronchoconstriction and lung inflammation
FR2739029B1 (fr) 1995-09-21 1997-11-21 Roussel Uclaf Nouvelle application therapeutique des composes antimineralo-corticoides
AU7286696A (en) 1995-10-13 1997-05-07 F. Hoffmann-La Roche Ag Antisense oligomers
CZ154898A3 (cs) 1995-11-21 1998-09-16 Icn Pharmaceuticals, Inc. Oligonukleotidy pro inhibici růstu nádorů zprostředkovaných IL-8 a receptorem IL-8
WO1997020942A1 (en) 1995-12-05 1997-06-12 Piao Yun Shang Hsd17b1 promoter, enhancer, silencer and use thereof
CN1215994A (zh) 1996-02-15 1999-05-05 国家健康学会 对治疗rsv感染有效的rna酶l激活剂和反义寡核苷酸
US5955590A (en) 1996-07-15 1999-09-21 Worcester Foundation For Biomedical Research Conjugates of minor groove DNA binders with antisense oligonucleotides
US6046004A (en) 1997-02-27 2000-04-04 Lorne Park Research, Inc. Solution hybridization of nucleic acids with antisense probes having modified backbones
JPH1142091A (ja) 1997-07-25 1999-02-16 Toagosei Co Ltd アンチセンス核酸化合物
US6391311B1 (en) 1998-03-17 2002-05-21 Genentech, Inc. Polypeptides having homology to vascular endothelial cell growth factor and bone morphogenetic protein 1
CA2248762A1 (en) 1997-10-22 1999-04-22 University Technologies International, Inc. Antisense oligodeoxynucleotides regulating expression of tnf-.alpha.
ES2312205T3 (es) 1998-03-10 2009-02-16 Genentech, Inc. Nuevo polipeptido y acidos nucleicos que lo codifican.
HUP0101809A3 (en) 1998-03-11 2002-07-29 Endorech Inc Sainte Foy Inhibitors of type 5 and type 3 17betha-hydroxysteroid dehydrogenase and methods for their use
US6007995A (en) 1998-06-26 1999-12-28 Isis Pharmaceuticals Inc. Antisense inhibition of TNFR1 expression
US6013522A (en) 1999-02-23 2000-01-11 Isis Pharmaceuticals Inc. Antisense inhibition of human Smad1 expression
US6025198A (en) 1999-06-25 2000-02-15 Isis Pharmaceuticals Inc. Antisense modulation of Ship-2 expression
US6033910A (en) 1999-07-19 2000-03-07 Isis Pharmaceuticals Inc. Antisense inhibition of MAP kinase kinase 6 expression
FR2801218B1 (fr) 1999-11-23 2001-12-28 Hoechst Marion Roussel Inc Compositions pharmaceutiques comprenant de la trimegestone, leurs procedes de preparation ainsi que le conditionnement primaire les renfermant
US7754709B2 (en) 2003-06-10 2010-07-13 Solvay Pharmaceuticals Bv Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds
US20090169585A1 (en) 2003-10-23 2009-07-02 Resveratrol Partners, Llc Resveratrol-Containing Compositions And Their Use In Modulating Gene Product Concentration Or Activity
US20050158376A1 (en) 2003-10-23 2005-07-21 Sardi William F. Dietary supplement and method of processing same
US20080299042A1 (en) 2004-04-30 2008-12-04 Biogen Idec Ma Inc. Membrane Associated Molecules
US7820380B2 (en) 2004-05-07 2010-10-26 Celera Corporation Genetic polymorphisms associated with liver fibrosis
FR2904000A1 (fr) 2006-07-19 2008-01-25 Galderma Res & Dev S N C Snc Modulateurs de hsd17b7 dans le traitement de l'acne ou de l'hyperseborrhee
US20080300170A1 (en) 2006-09-01 2008-12-04 Cohava Gelber Compositions and methods for diagnosis and treatment for type 2 diabetes
US7951776B2 (en) 2006-09-01 2011-05-31 American Type Culture Collection Methods for treatment of type 1 diabetes
US20090203602A1 (en) 2006-09-01 2009-08-13 Cohava Gelber Compositions and methods for diagnosis and treatment of type 2 diabetes
US20100267052A1 (en) 2006-09-01 2010-10-21 American Type Culture Collection Compositions and methods for diagnosis and treatment of type 2 diabetes
WO2008091873A2 (en) 2007-01-24 2008-07-31 Dana-Farber Cancer Institute, Inc. Compositions and methods for the identification, assessment, prevention and therapy of thymic lymphoma or hamartomatous tumours
JP2010540444A (ja) 2007-09-20 2010-12-24 レスベラトロル パートナーズ， エルエルシー 遺伝子産物の濃縮または活性を調節するためのレスベラトロールを含む組成物
EP2298359A1 (en) 2008-06-04 2011-03-23 Kyowa Hakko Kirin Co., Ltd. Nucleic acid capable of controlling degranulation of mast cell
WO2010028110A2 (en) 2008-09-04 2010-03-11 Board Of Regents, The University Of Texas System Sequence variations in pnpla3 associated with hepatic steatosis
US20100209427A1 (en) 2008-09-24 2010-08-19 Yu Li Lysine acetylation sites
EP2177615A1 (en) 2008-10-10 2010-04-21 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Method for a genome wide identification of expression regulatory sequences and use of genes and molecules derived thereof for the diagnosis and therapy of metabolic and/or tumorous diseases
JPWO2010064702A1 (ja) 2008-12-05 2012-05-10 国立大学法人 東京大学 癌の予後を予測するためのバイオマーカー
CA2697169A1 (en) 2009-03-18 2010-09-18 David Stojdl Compositions and methods for augmenting activity of oncolytic viruses
WO2010120526A2 (en) 2009-03-31 2010-10-21 Emory University Methods and systems for screening for and diagnosing dna methylation associated with autism spectrum disorders
US9051567B2 (en) 2009-06-15 2015-06-09 Tekmira Pharmaceuticals Corporation Methods for increasing efficacy of lipid formulated siRNA
ES2657737T3 (es) 2009-07-15 2018-03-06 Calimmune Inc. Vector dual para la inhibición del virus de la inmunodeficiencia humana
WO2011006214A1 (en) 2009-07-16 2011-01-20 Peter Maccallum Cancer Institute Method of detecting radiation exposure and adverse toxicity thereto
CA2781654A1 (en) 2009-11-25 2011-06-03 Hua Gong Novel genomic biomarkers for irritable bowel syndrome diagnosis
WO2011084747A2 (en) 2009-12-21 2011-07-14 The Johns Hopkins University Compositions and methods for somatic tissue induced pluripotent stem cells having an endoderm origin
US20130029873A1 (en) 2010-04-12 2013-01-31 University Health Network Methods and compositions for diagnosing pulmonary fibrosis subtypes and assessing the risk of primary graft dysfunction after lung transplantation
WO2011128096A1 (en) 2010-04-16 2011-10-20 Roche Diagnostics Gmbh Polymorphism markers for predicting response to interleukin-6 receptor-inhibiting monoclonal antibody drug treatment
DK2569446T3 (en) 2010-05-12 2018-10-29 Steven E Schutzer DIAGNOSTIC MARKERS FOR NEUROPsychiatric Disease
US8945847B2 (en) 2010-05-24 2015-02-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Methods and kits for ascertaining biosafety of an agent
US20120058088A1 (en) 2010-06-28 2012-03-08 Resveratrol Partners, Llc Resveratrol-Containing Compositions And Methods Of Use
CA2804763C (en) 2010-07-14 2023-01-03 The Regents Of The University Of California Biomarkers for diagnosis of transient ischemic attacks
WO2012031008A2 (en) 2010-08-31 2012-03-08 The General Hospital Corporation Cancer-related biological materials in microvesicles
WO2012052953A1 (en) 2010-10-20 2012-04-26 Fondazione Centro San Raffaele Del Monte Tabor MiRNA
WO2012058097A1 (en) 2010-10-26 2012-05-03 Buck Institute For Age Research Downregulation of sine/alu retrotransposon transcription to induce or restore proliferative capacity and/or pluripotency to a stem cell
CA2817256A1 (en) 2010-11-12 2012-05-18 The General Hospital Corporation Polycomb-associated non-coding rnas
US9920317B2 (en) 2010-11-12 2018-03-20 The General Hospital Corporation Polycomb-associated non-coding RNAs
WO2012070014A2 (en) 2010-11-26 2012-05-31 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Identification of novel cell surface markers for pancreatic progenitor cells and definite endodermal cells
US20140057800A1 (en) 2010-12-16 2014-02-27 Norwegian Univeristy of Science and Technology (NTNU) Single nucleotide polymorphism associated with risk of insulin resistance development
EP2655621B1 (en) 2010-12-20 2018-05-23 The General Hospital Corporation Polycomb-associated non-coding rnas
WO2012151346A1 (en) 2011-05-03 2012-11-08 Dermachip Inc. Expression signatures of genes and gene networks associated with skin aging
GB201112246D0 (en) 2011-07-15 2011-08-31 Univ Birmingham Diagnosis of alzheimer's disease
US20130079241A1 (en) 2011-09-15 2013-03-28 Jianhua Luo Methods for Diagnosing Prostate Cancer and Predicting Prostate Cancer Relapse
WO2013126565A1 (en) 2012-02-24 2013-08-29 Lunyak Victoria V Downregulation of sine/alu retrotransposon transcription to induce or restore proliferative capacity and/or pluripotency to a stem cell
WO2013166264A2 (en) 2012-05-02 2013-11-07 University Of Georgia Research Foundation, Inc. Methods for altering virus replication
US9677138B2 (en) 2012-05-20 2017-06-13 Trustees Of Boston University Methods and systems for monitoring, diagnosing, and treating chronic obstructive pulmonary disease
AU2013266968B2 (en) 2012-05-25 2017-06-29 Emmanuelle CHARPENTIER Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
EP2864791A2 (en) 2012-06-20 2015-04-29 Leibniz - Institut für Analytische Wissenschaften - ISAS - E.V. Specific biomarkers for hepatocellular carcinoma (hcc)
US20140004153A1 (en) 2012-07-02 2014-01-02 Lancell, L.L.C. Use of somatic mutations in the extracellular domain of transmembrane proteins in a patient's tumor as immunogens for active humoral immunotherapy of cancer
WO2014028946A2 (en) 2012-08-17 2014-02-20 The Broad Institute, Inc. Modulators of hepatic lipoprotein metabolism
US9375433B2 (en) 2012-09-26 2016-06-28 Tangent Reprofiling Limited Modulators of androgen synthesis
NZ706067A (en) 2012-09-26 2016-07-29 Tangent Reprofiling Ltd Modulators of androgen synthesis
IL292159B1 (en) 2012-12-05 2026-04-01 Alnylam Pharmaceuticals Inc PCSK9 iRNA compositions and methods of using them
EP4331620A3 (en) 2012-12-07 2024-12-04 Translate Bio, Inc. Lipidic nanoparticles for mrna delivery
EP2970940B1 (en) 2013-03-14 2018-07-25 Translate Bio, Inc. Mrna therapeutic compositions and use to treat diseases and disorders
US20160032395A1 (en) 2013-03-14 2016-02-04 Elai Davicioni Cancer biomarkers and classifiers and uses thereof
CN105247075B (zh) 2013-03-15 2019-02-15 威拉赛特公司 用于诊断肺病的生物标记物及其使用方法
US20140329704A1 (en) 2013-03-28 2014-11-06 President And Fellows Of Harvard College Markers for mature beta-cells and methods of using the same
GB201306536D0 (en) 2013-04-10 2013-05-22 Gt Biolog Ltd Polypeptide and immune modulation
WO2014196957A1 (en) 2013-06-03 2014-12-11 Nestec Sa Methods for diagnosing chronic valvular disease
US9574241B2 (en) 2013-06-03 2017-02-21 The Trustees Of Columbia University In The City Of New York Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T-cell lymphomas
CN105683379A (zh) 2013-06-17 2016-06-15 布罗德研究所有限公司 用于对有丝分裂后细胞的疾病和障碍进行靶向和建模的系统、方法和组合物的递送、工程化和优化
RU2716420C2 (ru) 2013-06-17 2020-03-11 Те Брод Инститьют Инк. Доставка и применение систем crispr-cas, векторов и композиций для целенаправленного воздействия и терапии в печени
US20150079062A1 (en) 2013-07-12 2015-03-19 Patrick J. Casey Method for harvesting, processing, and storage of proteins from the mammalian feto-placental unit and use of such proteins in compositions and medical treatment
EP3019186A4 (en) 2013-07-12 2017-03-29 Patrick J. Casey Method for the harvesting, processing, and storage of proteins from the mammalian feto-placental unit and use of such proteins in compositions and medical treatment
RU2545990C2 (ru) 2013-07-16 2015-04-10 Государственное бюджетное учреждение здравоохранения города Москвы Московский клинический научно-практический центр Департамента здравоохранения города Москвы Способ дифференциальной диагностики стеатоза печени и стеатогепатита
ES3032935T3 (en) 2013-10-22 2025-07-29 Translate Bio Inc Lipid formulations for delivery of messenger rna
GB201320061D0 (en) 2013-11-13 2013-12-25 Electrophoretics Ltd Materials nad methods for diagnosis and prognosis of liver cancer
WO2015169971A1 (en) 2014-05-09 2015-11-12 Tangent Reprofiling Limited Modulators of androgen synthesis
EP3155116A4 (en) 2014-06-10 2017-12-27 Massachusetts Institute Of Technology Method for gene editing
US10588980B2 (en) 2014-06-23 2020-03-17 Novartis Ag Fatty acids and their use in conjugation to biomolecules
WO2016004387A1 (en) 2014-07-02 2016-01-07 H. Lee Moffitt Cancer Center And Research Institute, Inc. Gene expression signature for cancer prognosis
WO2016009246A1 (en) 2014-07-14 2016-01-21 Casey Patrick J Method for the harvesting, processing, and storage of proteins from the mammalian feto-placental unit and use of such proteins in compositions and medical treatment
WO2016028638A1 (en) 2014-08-18 2016-02-25 Drexel University Methods, computer-readable media, and systems for assessing samples and wounds, predicting whether a wound will heal, and monitoring effectiveness of a treatment
US20170335396A1 (en) 2014-11-05 2017-11-23 Veracyte, Inc. Systems and methods of diagnosing idiopathic pulmonary fibrosis on transbronchial biopsies using machine learning and high dimensional transcriptional data
CA2976445A1 (en) 2015-02-13 2016-08-18 Alnylam Pharmaceuticals, Inc. Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof
CN104698108B (zh) 2015-03-26 2016-11-09 中国药科大学 一种利用固定化酶筛选I型17β羟类固醇脱氢酶抑制剂的方法
EP3159407A1 (en) 2015-10-23 2017-04-26 Silence Therapeutics (London) Ltd Guide rnas, methods and uses
EP3387129A1 (en) 2015-12-10 2018-10-17 Alnylam Pharmaceuticals, Inc. STEROL REGULATORY ELEMENT BINDING PROTEIN (SREBP) CHAPERONE (SCAP) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
ES2903394T3 (es) 2015-12-14 2022-04-01 Cold Spring Harbor Laboratory Composiciones para el tratamiento de la retinitis pigmentosa 13
EP3390666A4 (en) 2015-12-14 2019-08-07 Cold Spring Harbor Laboratory COMPOSITIONS AND METHODS OF TREATING NURSE DISEASES
EP3390635A4 (en) 2015-12-14 2019-05-01 Cold Spring Harbor Laboratory Antisense oligomers for the treatment of a tuberous sclerosis complex
JP7049249B2 (ja) 2015-12-14 2022-04-06 コールド スプリング ハーバー ラボラトリー 中枢神経系疾患の処置のための組成物および方法
JP2019500345A (ja) 2015-12-14 2019-01-10 コールド スプリング ハーバー ラボラトリー 肝臓病の処置のための組成物および方法
CA3005245A1 (en) 2015-12-14 2017-06-22 Cold Spring Harbor Laboratory Antisense oligomers for treatment of alagille syndrome
JP7036723B2 (ja) 2015-12-14 2022-03-15 コールド スプリング ハーバー ラボラトリー 眼疾患の処置のための組成物および方法
US20190071795A1 (en) 2016-03-09 2019-03-07 Molecular Stethoscope, Inc. Methods and systems for detecting tissue conditions
CA3221950A1 (en) 2016-03-16 2017-09-21 Spogen Biotech Inc. Methods for promoting plant health using free enzymes and microorganisms that overexpress enzymes
WO2017191274A2 (en) 2016-05-04 2017-11-09 Curevac Ag Rna encoding a therapeutic protein
US10036024B2 (en) 2016-06-03 2018-07-31 Purdue Research Foundation siRNA compositions that specifically downregulate expression of a variant of the PNPLA3 gene and methods of use thereof for treating a chronic liver disease or alcoholic liver disease (ALD)
GB201609977D0 (en) 2016-06-08 2016-07-20 Cancer Rec Tech Ltd Chemosensitivity predictive biomarkers
US10767175B2 (en) 2016-06-08 2020-09-08 Agilent Technologies, Inc. High specificity genome editing using chemically modified guide RNAs
SG10202106058WA (en) 2016-12-08 2021-07-29 Intellia Therapeutics Inc Modified guide rnas
AU2017374042C1 (en) 2016-12-09 2024-07-11 Acuitas Therapeutics, Inc. Delivery of target specific nucleases
AU2017378427A1 (en) 2016-12-14 2019-06-20 Ligandal, Inc. Methods and compositions for nucleic acid and protein payload delivery
RU2019126483A (ru) 2017-01-23 2021-02-24 Ридженерон Фармасьютикалз, Инк. Варианты 17-бета-гидроксистероиддегидрогеназы 13 (hsd17b13) и их применение
CN118581154A (zh) 2017-06-02 2024-09-03 国家健康与医学研究院 用于遗传障碍的基因疗法的基因组编辑手段和结合病毒载体的基因疗法
AU2018348195B2 (en) * 2017-10-11 2025-05-15 Regeneron Pharmaceuticals, Inc. Inhibition of HSD17B13 in the treatment of liver disease in patients expressing the PNPLA3 I148M variation
AU2019239971B2 (en) 2018-03-21 2025-09-11 Regeneron Pharmaceuticals, Inc. 17beta-hydroxysteroid dehydrogenase type 13 (HSD17b13) iRNA compositions and methods of use thereof
US20210000906A1 (en) 2018-03-21 2021-01-07 Ionis Pharmaceuticals, Inc. Modulation of hsd17b13 expression
US11690921B2 (en) 2018-05-18 2023-07-04 Sangamo Therapeutics, Inc. Delivery of target specific nucleases
AU2019282824C1 (en) 2018-06-08 2026-04-23 Intellia Therapeutics, Inc. Modified guide RNAS for gene editing
CA3103528A1 (en) 2018-06-19 2019-12-26 The Board Of Regents Of The University Of Texas System Lipid nanoparticle compositions for delivery of mrna and long nucleic acids
US11957687B2 (en) 2019-07-02 2024-04-16 Regeneron Pharmaceuticals, Inc. Modulators of HSD17B13 and methods of use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103520724A (zh) * 2013-10-23 2014-01-22 北京美森生物医药科技有限公司 Hsd17b13蛋白或其编码基因的抑制剂的新用途
WO2017048620A1 (en) * 2015-09-14 2017-03-23 Alnylam Pharmaceuticals, Inc. Polynucleotide agents targeting patatin-like phospholipase domain containing 3 (pnpla3) and methods of use thereof

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BRATATI KAHALI等: "Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease", 《SEMINARS IN LIVER DISEASE》, vol. 35, no. 4, pages 375 - 391, XP055530703, DOI: 10.1055/s-0035-1567870 *
CHRISTOPHER J.DANFORD;ZEMIN YAO;Z.GORDON JIANG;: "Non-alcoholic fatty liver disease: a narrative review of genetics", THE JOURNAL OF BIOMEDICAL RESEARCH, no. 06, pages 1 - 2 *
DEBORAH EDELMAN等: "Genetic analysis of nonalcoholic fatty liver disease within a Caribbean–Hispanic population", 《MOLECULAR GENETICS & GENOMIC MEDICINE》, vol. 3, no. 6, pages 558 - 569, XP055530684, DOI: 10.1002/mgg3.168 *
JIAN-HUA SHEN等: "The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis", 《JOURNAL OF LIPID RESEARCH》, vol. 56, pages 167 - 175, XP055530673, DOI: 10.1194/jlr.M048777 *
KENTARO ONIKI等: "Influence of the PNPLA3 rs738409 Polymorphism on Non-Alcoholic Fatty Liver Disease and Renal Function among Normal Weight Subjects", 《PLOS ONE》, pages 1 - 14 *
KIKUKO HOTTA等: "Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease", 《BMC MEDICAL GENETICS》, vol. 11, no. 172, pages 1 - 10 *
WEN SU等: "Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease", PNAS, vol. 111, no. 31, pages 11437 - 11442, XP055473896, DOI: 10.1073/pnas.1410741111 *
XING, XIAOHUA等: "Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by iTRAQ-based quantitative proteomics", JOURNAL OF PROTEOMICS, vol. 128, pages 262 - 271 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112626199A (zh) * 2021-01-04 2021-04-09 杭州艾迪康医学检验中心有限公司 检测慢性肝炎转化为肝硬化的风险预测位点的引物和方法
CN118813778A (zh) * 2024-07-01 2024-10-22 北京泛生子基因科技有限公司 一种试剂盒、使用方法及存储介质

Also Published As

Publication number Publication date
JP2020536560A (ja) 2020-12-17
US10961583B2 (en) 2021-03-30
US11702700B2 (en) 2023-07-18
NZ763161A (en) 2026-02-27
RU2020115526A3 (https=) 2021-11-26
JP7434151B2 (ja) 2024-02-20
EP4234719A2 (en) 2023-08-30
EP3695012A1 (en) 2020-08-19
US12286677B2 (en) 2025-04-29
EP3695012B1 (en) 2023-03-08
AU2018348195A1 (en) 2020-04-23
IL273550B2 (en) 2025-09-01
RU2020115526A (ru) 2021-11-12
US20190106749A1 (en) 2019-04-11
IL319615A (en) 2025-05-01
AU2025203267A1 (en) 2025-05-29
WO2019075181A1 (en) 2019-04-18
EP4685243A3 (en) 2026-03-25
EP4234719A3 (en) 2023-10-18
US20230383353A1 (en) 2023-11-30
JP2026016717A (ja) 2026-02-03
IL273550B1 (en) 2025-05-01
MX2020003561A (es) 2020-08-03
KR20200062314A (ko) 2020-06-03
EP4685243A2 (en) 2026-01-28
US20250305050A1 (en) 2025-10-02
EP4234719B1 (en) 2025-11-26
JP7770438B2 (ja) 2025-11-14
SG11202003254SA (en) 2020-05-28
KR20240125690A (ko) 2024-08-19
AU2018348195B2 (en) 2025-05-15
JP2024045454A (ja) 2024-04-02
US20210246508A1 (en) 2021-08-12
IL273550A (en) 2020-05-31
KR102694809B1 (ko) 2024-08-16
CA3078883A1 (en) 2019-04-18

Similar Documents

Publication Publication Date Title
KR102694809B1 (ko) Pnpla3 i148m 변이를 발현하는 환자의 간 질환의 치료에서의 hsd17b13의 저해
AU2023202663B2 (en) Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) variants and uses thereof
KR102657306B1 (ko) 전립선암의 진단 및 치료에서 필라민을 포함하는 마커의 용도
CN101874120B (zh) 作为用于乳腺癌风险评估、诊断、预后和治疗的标记的chr2和chr16的遗传性变型
KR20230124915A (ko) 세포 사멸 유도 dffa 유사 이펙터 b(cideb) 억제제를 이용한 간 질환의 치료
CN101687050A (zh) 用于鉴别原发起源不明的癌的起源的方法和材料
KR102613599B1 (ko) 뇌경색 발증 리스크 예측 방법
TW201632629A (zh) 用於癌症診斷與預後的方法
KR20150023904A (ko) 전립선암의 진단 및 치료에서의 마커의 용도
CN101784675A (zh) 用于剥脱性综合征和青光眼的诊断、预后和治疗的标记物的chr 15q24上的遗传变异
US20030099958A1 (en) Diagnosis and treatment of vascular disease
CN102459645B (zh) 作为前列腺癌标记的磷酸二酯酶9a
TWI849576B (zh) 基因標記的用途
KR101114033B1 (ko) 단일염기다형을 포함하는 폴리뉴클레오티드, 이를 포함하는 마이크로어레이 및 진단키트, 및 이를 이용한 분석방법
CN114277123A (zh) 与精神分裂症相关的含有snp位点的多核苷酸和用途
CN113825839A (zh) 用固醇调节元件结合蛋白切割激活蛋白(scap)抑制剂治疗脂质水平升高
US20090258344A1 (en) Methods for identifying risk of breast cancer and treatments thereof
KR101090742B1 (ko) Ｈｅｒ－２ 유전자를 이용한 폐암 감수성 진단용 마커 및 이를 이용한 폐암 감수성 진단 방법
CN114222588A (zh) 巨噬细胞刺激1受体(mst1r)变体及其用途
KR20050008644A (ko) 위암에서의 유전자 발현 프로파일
CA2441701C (en) Detection of il4 and il13 polymorphisms in determination of type 1 diabetes susceptibility
JP2004000115A (ja) 糖尿病の発症危険性判定方法
KR20240043753A (ko) Wnt 패밀리 구성원 5B(WNT5B) 저해제를 사용한 감소된 골밀도의 치료
KR20130048240A (ko) Ｐｃｂｐ―１ 항원에 대한 모노클로날 항체, 및 그의 용도
WO2020260861A1 (en) Her2 gene splice variants

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB03 Change of inventor or designer information
CB03 Change of inventor or designer information

Inventor after: Xin Yurong

Inventor after: J. Gromada

Inventor after: Cheng Xiping

Inventor after: F. Dewey

Inventor after: T. Terslovic dostar

Inventor after: C. Shulman

Inventor after: A. Barras

Inventor after: N. Abu Husen

Inventor before: Xin Yurong

Inventor before: J. Gromada

Inventor before: Cheng Xiping

Inventor before: F. Dewey

Inventor before: T. Terslovic dostar

Inventor before: C. Shulman