WO2025015182A2 - Compositions et procédés de traitement de l'auto-immunité - Google Patents

Compositions et procédés de traitement de l'auto-immunité Download PDF

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Publication number
WO2025015182A2
WO2025015182A2 PCT/US2024/037626 US2024037626W WO2025015182A2 WO 2025015182 A2 WO2025015182 A2 WO 2025015182A2 US 2024037626 W US2024037626 W US 2024037626W WO 2025015182 A2 WO2025015182 A2 WO 2025015182A2
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WO
WIPO (PCT)
Prior art keywords
pkg1
antagonist
agonist
effective amount
subject
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
PCT/US2024/037626
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English (en)
Other versions
WO2025015182A3 (fr
Inventor
Timothy NIEWOLD
Ruth FERNANDEZ RUIZ
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.)
New York Society for Relief of Ruptured and Crippled
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New York Society for Relief of Ruptured and Crippled
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Publication date
Application filed by New York Society for Relief of Ruptured and Crippled filed Critical New York Society for Relief of Ruptured and Crippled
Publication of WO2025015182A2 publication Critical patent/WO2025015182A2/fr
Publication of WO2025015182A3 publication Critical patent/WO2025015182A3/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid

Definitions

  • SLE Systemic lupus erythematosus
  • SLE systemic lupus erythematosus
  • PPKG1 codes for the cyclic GMP-dependent protein kinase I (PKG1).
  • RhoA/ROCK pathway affects PPKG1 gene expression and modulates the activity of the RhoA/ROCK pathway.
  • SLE patients exhibit higher ROCK activity in circulating immune cells compared to healthy individuals.
  • ROCK inhibitors decrease IFNa production by plasmacytoid dendritic cell (pDC) and downregulate IL-21 and IL- 17 secretion by T helper (Th) 17 cells.
  • the RhoA/ROCK pathway also regulates cytoskeleton components associated with microtubule and actin polymerization, which are crucial for pDC clustering and IFNa production.
  • provided herein is a method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, the method comprising upregulating cyclic GMP-dependent protein kinase I (PKG1) in the subject.
  • a method of decreasing type I IFN production in a subject in need thereof the method comprising upregulating cyclic GMP-dependent protein kinase I (PKG1) in the subject.
  • PKG1 is upregulated by administering a PKG1 agonist.
  • the method comprises administering a PKG1 agonist and a ROCKl antagonist.
  • FIG. 1 shows a schematic overview of PKG1 stimulation to inhibit of the RhoA/ROCK pathway and reduce TLR-induced type I interferon production.
  • FIG. 2 provides an overview of methods for assessing the effects of a PKG1 agonist or ROCK inhibitor on IFN production and Treg differentiation.
  • FIG. 3 shows baseline expression of PKG1 in LCLs with the AA, AC, of CC rs7897633 genotypes.
  • FIG. 5 A and FIG. 5B show type I interferon production by LCLs (FIG. 5 A) and PBMCs (FIG. B) at baseline and after treatment with R848 (5 pM) +/- the PKG1 agonist 8-CPT-cGMP (200 pM).
  • IFN scores were determined by the WISH cell functional assay. *p ⁇ 0.05 by Wilcoxon matched-pairs signed-rank test.
  • FIGs. 6A and 6B show the greater abundance of PKG1 and VASP phosphorylation in non-risk allele homozygotes.
  • FIG. 6A Representative Western blot analysis comparing PKG1 (80 KDa) abundance, normalized for beta-actin (45 KDa), in different rs7897633 genotype categories.
  • FIG. 7 shows R848-induced type I interferon production by B lymphoblastoid cell lines after treatment with the PKG1 agonist (PKG la) 8-CPTcGMP.
  • FIG. 8 shows R848-induced type I interferon production after treatment with the PKG1 agonist8-CPT-cGMP and the non-selective ROCK inhibitor Y27632.
  • Each symbol represents a cell line (assessed by duplicates).
  • NS by Wilcoxon test.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des méthodes de traitement de maladies auto-immunes telles que le lupus érythémateux disséminé (SLE) chez un sujet par régulation à la hausse de la protéine kinase I dépendante du GMP cyclique (PKG1).
PCT/US2024/037626 2023-07-12 2024-07-11 Compositions et procédés de traitement de l'auto-immunité Pending WO2025015182A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363513260P 2023-07-12 2023-07-12
US63/513,260 2023-07-12

Publications (2)

Publication Number Publication Date
WO2025015182A2 true WO2025015182A2 (fr) 2025-01-16
WO2025015182A3 WO2025015182A3 (fr) 2025-04-03

Family

ID=94216368

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/037626 Pending WO2025015182A2 (fr) 2023-07-12 2024-07-11 Compositions et procédés de traitement de l'auto-immunité

Country Status (1)

Country Link
WO (1) WO2025015182A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1351707B9 (fr) * 2001-01-09 2012-01-25 Baylor Research Institute Traitements de maladies auto-immunes chez un sujet et techniques diagnostiques i in vitro /i
DK3359688T3 (da) * 2015-10-05 2021-08-23 Biogen Ma Inc Molekylære signaturer til anvendelse til diagnose og analyse af respons på behandling af autoimmune sygdomme
US20240018125A1 (en) * 2020-09-28 2024-01-18 Ermium Therapeutics Cyclic isothiourea derivatives as cxcr4 modulators

Also Published As

Publication number Publication date
WO2025015182A3 (fr) 2025-04-03

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