[go: up one dir, main page]

MX2023012559A - Métodos de tratamiento para la distrofia muscular. - Google Patents

Métodos de tratamiento para la distrofia muscular.

Info

Publication number
MX2023012559A
MX2023012559A MX2023012559A MX2023012559A MX2023012559A MX 2023012559 A MX2023012559 A MX 2023012559A MX 2023012559 A MX2023012559 A MX 2023012559A MX 2023012559 A MX2023012559 A MX 2023012559A MX 2023012559 A MX2023012559 A MX 2023012559A
Authority
MX
Mexico
Prior art keywords
muscular dystrophy
treatment methods
patient
conjugate
dmd
Prior art date
Application number
MX2023012559A
Other languages
English (en)
Inventor
Lilly East
Huadong Sun
Jon Tinsley
Jake Elkins
Original Assignee
Sarepta Therapeutics 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
Application filed by Sarepta Therapeutics Inc filed Critical Sarepta Therapeutics Inc
Publication of MX2023012559A publication Critical patent/MX2023012559A/es

Links

Classifications

    • 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
    • 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
    • C12N15/1138—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 receptors or cell surface proteins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/314—Phosphoramidates
    • C12N2310/3145—Phosphoramidates with the nitrogen in 3' or 5'-position
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3233—Morpholino-type ring
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3513—Protein; Peptide
    • 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
    • C12N2320/33—Alteration of splicing
    • 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
    • C12N2320/35—Special therapeutic applications based on a specific dosage / administration regimen

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Se describen nuevos regímenes de dosificación para tratar la distrofia muscular en un paciente que sufre de distrofia muscular de Duchenne (DMD) con un oligonucleótido conjugado antisentido que provoca la omisión de un exón en el gen de la distrofina humana. También se describe un método para tratar a un paciente con un conjugado de CPP de oligómero antisentido y un suplemento de magnesio.
MX2023012559A 2021-04-30 2022-04-29 Métodos de tratamiento para la distrofia muscular. MX2023012559A (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202163182327P 2021-04-30 2021-04-30
US202163249721P 2021-09-29 2021-09-29
PCT/US2022/026887 WO2022232478A1 (en) 2021-04-30 2022-04-29 Treatment methods for muscular dystrophy

Publications (1)

Publication Number Publication Date
MX2023012559A true MX2023012559A (es) 2023-12-15

Family

ID=81749386

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2023012559A MX2023012559A (es) 2021-04-30 2022-04-29 Métodos de tratamiento para la distrofia muscular.

Country Status (11)

Country Link
US (1) US12286630B2 (es)
EP (1) EP4330395A1 (es)
JP (1) JP2024519451A (es)
KR (1) KR20240004609A (es)
AU (1) AU2022267324A1 (es)
BR (1) BR112023021849A2 (es)
CA (1) CA3216839A1 (es)
CO (1) CO2023016203A2 (es)
IL (1) IL307937A (es)
MX (1) MX2023012559A (es)
WO (1) WO2022232478A1 (es)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12018087B2 (en) 2018-08-02 2024-06-25 Dyne Therapeutics, Inc. Muscle-targeting complexes comprising an anti-transferrin receptor antibody linked to an oligonucleotide and methods of delivering oligonucleotide to a subject
WO2020028832A1 (en) 2018-08-02 2020-02-06 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies
US11168141B2 (en) 2018-08-02 2021-11-09 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies
US20220193250A1 (en) 2018-08-02 2022-06-23 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating facioscapulohumeral muscular dystrophy
US11969475B2 (en) 2021-07-09 2024-04-30 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating facioscapulohumeral muscular dystrophy
US11771776B2 (en) 2021-07-09 2023-10-03 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521063A (en) 1985-03-15 1996-05-28 Antivirals Inc. Polynucleotide reagent containing chiral subunits and methods of use
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5217866A (en) 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
JP2528107B2 (ja) 1985-03-15 1996-08-28 サマ−トン，ジエ−ムス ポリヌクレオチド測定試薬と方法
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
JPH07509133A (ja) 1992-07-17 1995-10-12 リボザイム・ファーマシューティカルズ・インコーポレイテッド 動物疾患の処置のための方法および剤
US5820873A (en) 1994-09-30 1998-10-13 The University Of British Columbia Polyethylene glycol modified ceramide lipids and liposome uses thereof
US5885613A (en) 1994-09-30 1999-03-23 The University Of British Columbia Bilayer stabilizing components and their use in forming programmable fusogenic liposomes
US5753613A (en) 1994-09-30 1998-05-19 Inex Pharmaceuticals Corporation Compositions for the introduction of polyanionic materials into cells
WO1999042091A2 (en) 1998-02-19 1999-08-26 Massachusetts Institute Of Technology Use of polycations as endosomolytic agents
US6683173B2 (en) 1998-04-03 2004-01-27 Epoch Biosciences, Inc. Tm leveling methods
US7070807B2 (en) 1999-12-29 2006-07-04 Mixson A James Branched histidine copolymers and methods for using same
AU2281201A (en) 1999-12-29 2001-07-09 A. James Mixson Histidine copolymer and methods for using same
CA3001404C (en) 2002-11-25 2020-07-28 Masafumi Matsuo Ena nucleic acid pharmaceuticals capable of modifying splicing of mrna precursors
EP1629105B1 (en) 2003-04-29 2010-09-01 AVI BioPharma, Inc. Compositions for enhancing transport and antisense efficacy of nucleic acid analog into cells
WO2009005793A2 (en) 2007-06-29 2009-01-08 Avi Biopharma, Inc. Tissue specific peptide conjugates and methods
US8076476B2 (en) 2007-11-15 2011-12-13 Avi Biopharma, Inc. Synthesis of morpholino oligomers using doubly protected guanine morpholino subunits
US8299206B2 (en) 2007-11-15 2012-10-30 Avi Biopharma, Inc. Method of synthesis of morpholino oligomers
WO2009127230A1 (en) 2008-04-16 2009-10-22 Curevac Gmbh MODIFIED (m)RNA FOR SUPPRESSING OR AVOIDING AN IMMUNOSTIMULATORY RESPONSE AND IMMUNOSUPPRESSIVE COMPOSITION
TWI541024B (zh) 2010-09-01 2016-07-11 日本新藥股份有限公司 反義核酸
JP5831455B2 (ja) 2010-09-30 2015-12-09 日本新薬株式会社 モルホリノ核酸誘導体
US9161948B2 (en) 2011-05-05 2015-10-20 Sarepta Therapeutics, Inc. Peptide oligonucleotide conjugates
JP6478632B2 (ja) 2011-05-05 2019-03-06 サレプタ セラピューティクス， インコーポレイテッド ペプチドオリゴヌクレオチドコンジュゲート
CN108611349A (zh) 2011-12-28 2018-10-02 日本新药株式会社 反义核酸
SG11201607095RA (en) 2014-03-12 2016-10-28 Nippon Shinyaku Co Ltd Antisense nucleic acids
CN111575282B (zh) 2014-06-17 2024-05-14 日本新药株式会社 反义核酸
CN108026531B (zh) 2015-09-15 2021-09-14 日本新药株式会社 反义核酸
NZ781029A (en) 2015-10-09 2025-07-25 Wave Life Sciences Ltd Oligonucleotide compositions and methods thereof
KR102824513B1 (ko) 2016-07-05 2025-06-25 바이오마린 테크놀로지스 비.브이. 유전적 장애 치료를 위한, 특징이 개선된, 비사이클릭 스캐폴드 모이어티를 포함하는 프리-mrna 스플라이스 스위칭 또는 조정 올리고뉴클레오티드
AU2017361784B2 (en) 2016-11-16 2021-07-15 Academisch Ziekenhuis Leiden Substances for targeting various selected organs or tissues
MD3554554T2 (ro) 2016-12-19 2022-12-31 Sarepta Therapeutics Inc Conjugați de oligomeri de omitere a exonului, pentru distrofie musculară
SG10202012839TA (en) 2016-12-19 2021-01-28 Sarepta Therapeutics Inc Exon skipping oligomer conjugates for muscular dystrophy
BR112019012664A2 (pt) 2016-12-19 2020-01-21 Sarepta Therapeutics Inc conjugados de oligômero de salto de éxon para distrofia muscular
MX2019008199A (es) 2017-01-06 2019-11-25 Avidity Biosciences Llc Composiciones de acido nucleico polipeptido y metodos de induccion de la omision de exon.
US20200282074A1 (en) 2017-09-22 2020-09-10 Avidity Biosciences, Inc. Nucleic acid-polypeptide compositions and methods of inducing exon skipping
MY209148A (en) 2018-06-26 2025-06-24 Nippon Shinyaku Co Ltd Composition comprising antisense oligonucleotide and use thereof for treatment of duchenne muscular dystrophy
WO2020028832A1 (en) 2018-08-02 2020-02-06 Dyne Therapeutics, Inc. Muscle targeting complexes and uses thereof for treating dystrophinopathies
JP7661218B2 (ja) 2018-11-02 2025-04-14 バイオマリン テクノロジーズ ベー．フェー． ジストロフィンエクソンスキッピングのための二重特異性アンチセンスオリゴヌクレオチド
CN113660938A (zh) 2019-01-30 2021-11-16 国立研究开发法人国立精神·神经医疗研究中心 核酸递送复合物
EP3955966A1 (en) * 2019-04-18 2022-02-23 Sarepta Therapeutics, Inc. Compositions for treating muscular dystrophy
EP3959319A4 (en) 2019-04-25 2023-06-07 Avidity Biosciences, Inc. NUCLEIC ACID COMPOSITIONS AND METHODS FOR MULTI-EXON SKIPPING

Also Published As

Publication number Publication date
US20230193282A1 (en) 2023-06-22
EP4330395A1 (en) 2024-03-06
BR112023021849A2 (pt) 2023-12-19
US12286630B2 (en) 2025-04-29
WO2022232478A1 (en) 2022-11-03
IL307937A (en) 2023-12-01
AU2022267324A1 (en) 2023-12-14
JP2024519451A (ja) 2024-05-14
CO2023016203A2 (es) 2024-02-15
CA3216839A1 (en) 2022-11-03
KR20240004609A (ko) 2024-01-11
AU2022267324A9 (en) 2023-12-21

Similar Documents

Publication Publication Date Title
CO2023016203A2 (es) Métodos de tratamiento para la distrofia muscular
Fujita et al. Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene
CO2024012425A2 (es) Conjugados de oligómero de morfolino fosforodiamidato
BR112013026494A2 (pt) composto, composição farmacêutica, método para tratar condição
MX2020002038A (es) Métodos para el tratamiento de distrofia muscular.
Fraile-Martinez et al. Understanding the basis of major depressive disorder in oncological patients: Biological links, clinical management, challenges, and lifestyle medicine
BR112018008344A2 (pt) molécula de ácido nucleico, composição farmacêutica, vetor ou célula, método para prevenir, tratar ou melhorar uma doença, e, uso de uma composição
MX2022012965A (es) Inhibición por crispr para la distrofia muscular facioscapulohumeral.
BR112023000428A2 (pt) Métodos e composições para tratar epilepsia
CO2022008664A2 (es) Ácido nucleico antisentido que induce la omisión del exón 50
Pulik et al. The role of miRNA and lncRNA in heterotopic ossification pathogenesis
Min et al. Restoration of cellular proliferation and characteristics of human tenocytes by vitamin D
Thomas et al. Tamoxifen metabolite endoxifen interferes with the polyamine pathway in breast cancer
MX2024013409A (es) Metodo de tratamiento de la distrofia muscular de duchenne
Zhu et al. DNA microarray reveals ZNF195 and SBF1 are potential biomarkers for gemcitabine sensitivity in head and neck squamous cell carcinoma cell lines
MX2023015395A (es) Tratamiento de enfermedades y trastornos relacionados con mst1.
CL2023000949A1 (es) Oligonucleótidos antisentido que se dirigen al exón 51 del gen de la distrofina
Othus et al. Prediction of CR on reinduction in patients with newly diagnosed acute myeloid leukemia given intensive induction regimens: a report from SWOG and Cleveland Clinic
PH12021551137A1 (en) Application of chidamide
AR132602A1 (es) Oligonucleótidos de omisión de exón de distrofina
Knower et al. Intracrine oestrogen production and action in breast cancer: an epigenetic focus
Patmore et al. Mantle Cell Lymphoma Management and Outcome in the UK's Population-Based Haematological Malignancy Research Network
Cione et al. Strength training and sarcopenia—a mandatory link: focus on MicroRNAs
Beckett et al. Modulation of MicroRNA by Vitamin D in Cancer Studies
Wang et al. POS0398 adiponectin induces synovial angiogenesis in rheumatoid arthritis through metabolic remodeling