IP Library › Granted Patent US 12,534,762
Granted Patent B2
US 12,534,762 · App. 17/280,411 · Granted Jan 27, 2026

Treating atopic dermatitis by targeting the WNT pathway

Inventors: Xi He (Jamaica Plain, MA); Maorong Chen (Jamaica Plain, MA)
Assignee: Children's Medical Center Corporation
C12Q1/6883A61K45/06A61P35/00
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Quick Facts
Patent No.
US 12,534,762
App. No.
17/280,411
Granted
Jan 27, 2026
Kind
B2
Abstract

Methods of treating subjects with atopic dermatitis, e.g., associated with mutations in the TMEM79 gene, using Wnt inhibitors, e.g., porcupine inhibitors.

Claims (31)

1 . A method of treating a subject who has atopic dermatitis (AD), the method comprising administering a therapeutically effective amount of a porcupine (PORCN) inhibitor to a subject in need thereof, wherein the porcupine (PORCN) inhibitor is selected from the group consisting of LGK974; C59; ETC-159; ETC-131; and IWP compounds.

2 . The method of claim 1 , wherein the subject has a mutation in TMEM79.

3 . A method of treating a subject who has atopic dermatitis (AD), the method comprising:

obtaining a sample comprising genomic DNA from the subject;

performing an assay to determine presence or absence of a mutation in TMEM79 in the genomic DNA from the subject; and

administering a therapeutically effective amount of a porcupine (PORCN) inhibitor to a subject who has a mutation in TMEM79 that is associated with AD, wherein the porcupine (PORCN) inhibitor is selected from the group consisting of LGK974; C59; ETC-159; ETC-131; and IWP compounds.

4 . The method of claim 3 , wherein performing an assay to determine the presence or absence of a mutation in TMEM79 comprises performing an assay to detect the presence of a mutation known to be associated with AD.

5 . The method of claim 3 , wherein performing an assay to determine the presence or absence of a mutation in TMEM79 comprises:

sequencing all or part of a TMEM79 gene;

comparing the sequence to a reference sequence in an unaffected subject;

identifying a sequence that differs from the reference sequence as a mutation;

determining whether the mutation has an effect on TMEM79 activity or expression; and

identifying a subject who has a sequence that differs from the reference sequence and reduces TMEM79 activity or expression as having a mutation in TMEM79 that is associated with AD.

6 . A method of treating a subject who has atopic dermatitis (AD), the method comprising:

obtaining a sample comprising affected skin cells from the subject;

performing an assay to determine a level or activity of TMEM79 in the cells from the subject;

detecting a reduction in level or activity of TMEM79 in the sample; and

administering a therapeutically effective amount of a porcupine (PORCN) inhibitor to a subject who has a reduced level or activity of TMEM79 in the sample, wherein the porcupine (PORCN) inhibitor is selected from the group consisting of LGK974; C59; ETC-159; ETC-131; and IWP compounds.

7 . The method of claim 1 , wherein the subject does not have a mutation in a filaggrin gene (FLG).

8 . The method of claim 1 , wherein the IWP compounds are selected from the group consisting of IWP-2, IWP-L6, GNF6231, Compound 4:

 and Compound 5:

9 . The method of claim 2 , wherein the mutation in TMEM79 is one of SEQ ID NOs: 1 to 18.

10 . The method of claim 9 , wherein the mutation that is associated with AD is a methionine at rs6684514.

11 . The method of claim 3 , wherein performing an assay to determine presence or absence of a mutation in TMEM79 comprises performing an assay to detect the presence of a mutation, wherein the mutation is one of SEQ ID NOs: 1 to 18.

12 . The method of claim 4 , wherein the mutation known to be associated with AD is a methionine at rs6684514.

13 . The method of claim 3 , wherein the IWP compounds are selected from the group consisting of IWP-2, IWP-L6, GNF6231, Compound 4:

 and Compound 5:

14 . The method of claim 3 , wherein the subject does not have a mutation in FLG.

15 . The method of claim 6 , wherein the IWP compounds are selected from the group consisting of IWP-2, IWP-L6, GNF6231, Compound 4:

 and Compound 5:

16 . The method of claim 6 , wherein the subject does not have a mutation in FLG.

Assignments (2)
CONFIRMATORY LICENSE Recorded Nov 22, 2023
From: BOSTON CHILDREN'S HOSPITAL
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065666/0121 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 21, 2021
From: HE, XI; CHEN, MAORONG
To: CHILDREN'S MEDICAL CENTER CORPORATION
Reel/Frame 056928/0242 →
Continuity (2)
Provisional Application 62738182 · Sep 28, 2018
Related Publication 20220033904A1 · Feb 3, 2022
References Cited (71)
US 7652043B2 · Beachy et al. · 2010 [cited by applicant]
US 20070219257A1 · Beachy et al. · 2007 [cited by applicant]
US 20160303137A1 · Radovich et al. · 2016 [cited by applicant]
WO WO2010101849 · 2010 [cited by applicant]
WO WO2013130364 · 2013 [cited by applicant]
WO WO2014175832 · 2014 [cited by applicant]
WO WO2014189466 · 2014 [cited by applicant]
WO WO2015094118 · 2015 [cited by applicant]
WO WO2015094119 · 2015 [cited by applicant]
WO WO2015187094 · 2015 [cited by applicant]
Duraiswamy, Athisayamani Jeyaraj, et al. (“Discovery and optimization of a porcupine inhibitor.” Journal of medicinal chemistry 58.15 (2015): 5889-5899). [cited by examiner]
Ho, Soo Yei, and Thomas H. Keller. (“The use of porcupine inhibitors to target Wnt-driven cancers.” Bioorganic & medicinal chemistry letters 25.23 (2015): 5472-5476). [cited by examiner]
Alwan et al., “UBPY-mediated epidermal growth factor receptor (EGFR) de-ubiquitination promotes EGFR degradation,” Journal of Biological Chemistry, Jan. 19, 2007, 282(3):1658-69. [cited by applicant]
Blagodatski et al., “Targeting the Wnt pathways for therapies,” Molecular and Cellular Therapies, Dec. 2014, 2(1), 15 pages. [cited by applicant]
Blanpain et al., “Epidermal stem cells of the skin,” Annu. Rev. Cell Dev. Biol., Nov. 10, 2006, 22:339-73. [cited by applicant]
Chen et al., “Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling,” Annals of the Rheumatic Diseases, Apr. 1, 2017, 76(4):773-8. [cited by applicant]
Chen et al., “Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer,” Nature Chemical Biology, Feb. 2009, 5(2):100-7. [cited by applicant]
Clevers, “Wnt/β-catenin signaling in development and discase,” Cell, Nov. 3, 2006, 127(3):469-80. [cited by applicant]
De Robertis et al., “Dorsal-ventral patterning and neural induction in Xenopus embryos,” Annu. Rev. Cell Dev. Biol., Jun. 2004, 20:285-308. [cited by applicant]
Dodge et al., “Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine,” Journal of Biological Chemistry, Jun. 29, 2012, 287(27):23246-54. [cited by applicant]
Duraiswamy et al., “Discovery and optimization of a porcupine inhibitor,” Journal of Medicinal Chemistry, Aug. 13, 2015, 58(15):5889-99. [cited by applicant]
Eichenfield et al., “Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis,” Journal of the American Academy of Dermatology, Feb. 1, 2014, 70(2):338-51. [cited by applicant]
Elias et al., “Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis,” Journal of Allergy and Clinical Immunology, Oct. 1, 2014, 134(4):781-91. [cited by applicant]
Emrick et al., “Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell-mediated histaminergic itch,” Proceedings of the National Academy of Sciences, Dec. 18, 2018, 115(51):E12091-100. [cited by applicant]
Esparza-Gordillo et al., “A common variant on chromosome 11q13 is associated with atopic dermatitis,” Nature Genetics, May 2009, 41(5):596-601. [cited by applicant]
Eubelen et al., “A molecular mechanism for Wnt ligand-specific signaling,” Science, Aug. 17, 2018, 361(6403), 77 pages. [cited by applicant]
Gammons et al., “Multiprotein complexes governing Wnt signal transduction,” Current Opinion in Cell Biology, Apr. 1, 2018, 51:42-9. [cited by applicant]
Glinka et al., “Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction,” Nature, Jan. 1998, 391(6665):357-62. [cited by applicant]
Hao et al., “ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner,” Nature, May 2012, 485(7397):195-200. [cited by applicant]
Heasman et al., “βCatenin signaling activity dissected in the early Xenopus embryo: a novel antisense approach, ” Developmental Biology, Jun. 1, 2000, 222(1):124-34. [cited by applicant]
Ho et al., “The use of porcupine inhibitors to target Wnt-driven cancers,” Bioorganic & Medicinal Chemistry Letters, Dec. 1, 2015, 25(23):5472-6. [cited by applicant]
Houben et al., “A keratinocyte's course of life,” Skin Pharmacology and Physiology, Dec. 21, 2007, 20(3):122-32. [cited by applicant]
Hu et al., “Loss-of-function mutations in filaggrin gene associate with psoriasis vulgaris in Chinese population,” Human Genetics, Jul. 2012, 131(7):1269-74. [cited by applicant]
Irvine et al., “Filaggrin mutations associated with skin and allergic diseases,” New England Journal of Medicine, Oct. 6, 2011, 365(14):1315-27. [cited by applicant]
Jiang et al., “Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases,” Molecular Cell, May 7, 2015, 58(3):522-33. [cited by applicant]
Jiang et al., “Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma,” Proceedings of the National Academy of Sciences, Jul. 30, 2013, 110(31):12649-54. [cited by applicant]
Kelleher et al., “Retracted: Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year,” Apr. 2015, 135(4), 930-5 e1. [cited by applicant]
Kim et al., “Ubiquitin-specific protease 8 is a novel prognostic marker in early-stage lung adenocarcinoma,” Pathology International, Jun. 2017, 67(6):292-301. [cited by applicant]
Koo et al., “Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors,” Nature, Aug. 2012, 488(7413):665-9. [cited by applicant]
Liu et al., “Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974,” Proceedings of the National Academy of Sciences, Dec. 10, 2013, 110(50):20224-9. [cited by applicant]
Ma et al., “Recurrent gain-of-function USP8 mutations in Cushing's disease,” Cell Research, Mar. 2015. 25(3):306-17. [cited by applicant]
MacDonald et al., “Wnt/β-catenin signaling: components, mechanisms, and diseases,” Developmental Cell, Jul. 21, 2009, 17(1):9-26. [cited by applicant]
Madan et al., “Wnt addiction of genetically defined cancers reversed by PORCN inhibition,” Oncogene, Apr. 2016, 35(17):2197-207. [cited by applicant]
Margolis et al., “The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort,” Journal of Allergy and Clinical Immunology, Oct. 1, 2012, 130(4):912-7. [cited by applicant]
Mizuno et al., “Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes,” Molecular Biology of the Cell, Nov. 2005, 16(11):5163-74. [cited by applicant]
Mukai et al., “Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt,” The EMBO Journal, Jul. 7, 2010, 29(13):2114-25. [cited by applicant]
Nemoto-Hasebe et al., “FLG mutation p. Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema,” British Journal of Dermatology, Dec. 2009, 161(6):1387-90. [cited by applicant]
Niehrs, “Regionally specific induction by the Spemann-Mangold organizer,” Nature Reviews Genetics, Jun. 2004, 5(6):425-34. [cited by applicant]
Niendorf et al., “Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo,” Molecular and Cellular Biology, Jul. 1, 2007, 27(13):5029-39. [cited by applicant]
Nomura et al., “Unique mutations in the [cited by applicant]
Oyoshi et al., “Cellular and molecular mechanisms in atopic dermatitis,” Advances in Immunology, Jan. 1, 2009, 102:135-226. [cited by applicant]
Palmer et al., “Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis,” Nature Genetics, Apr. 2006, 38(4):441-6. [cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2019/053502, dated Apr. 8, 2021, 11 pages. [cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2019/053502, dated Feb. 25, 2020, 15 pages. [cited by applicant]
Poulsen et al., “Pharmacophore model for Wnt/Porcupine inhibitors and its use in drug design,” Journal of Chemical Information and Modeling, Jul. 27, 2015, 55(7):1435-48. [cited by applicant]
Proffitt et al., “Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer,” Cancer Research, Jan. 15, 2013, 73(2):502-7. [cited by applicant]
Reincke et al., “Mutations in the deubiquitinase gene USP8 cause Cushing's disease,” Nature Genetics, Jan. 2015, 47(1):31-8. [cited by applicant]
Row et al., “The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation,” Journal of Biological Chemistry, May 5, 2006, 281(18):12618-24. [cited by applicant]
Sandilands et al., “Filaggrin in the frontline: role in skin barrier function and disease,” Journal of Cell Science, May 1, 2009, 122(9):1285-94. [cited by applicant]
Sasaki et al., “A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis, ” Journal of Aller… [cited by applicant]
Saunders et al., “Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects,” Journal of Allergy and Clinical Immunology, Nov. 1, 2013, 132(5):1121-9. [cited by applicant]
Spergel et al., “Atopic dermatitis and the atopic march,” Journal of Allergy and Clinical Immunology, Dec. 1, 2003, 112(6):S118-27. [cited by applicant]
Thomsen, “Atopic dermatitis: natural history, diagnosis, and treatment,” International Scholarly Research Notices, Apr. 2014, vol. 2014, 8 pages. [cited by applicant]
Tollefson et al., “Atopic dermatitis: skin-directed management,” Pediatrics, Dec. 1, 2014, 134(6):e1735-44. [cited by applicant]
Visser et al., “Impact of atopic dermatitis and loss-of-function mutations in the filaggrin gene on the development of occupational irritant contact dermatitis.” British Journal of Dermatology, Feb. 2013. 168(2):326-32. [cited by applicant]
Wang et al., “The development of highly potent inhibitors for porcupine,” Journal of Medicinal Chemistry, Mar. 28, 2013, 56(6):2700-4. [cited by applicant]
Xia et al., “USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization,” PLoS Biology, Jan. 10, 2012, 10(1):e1001238, 16 pages. [cited by applicant]
Yan et al., “High expression of ubiquitin-specific protease 8 (USP8) is associated with poor prognosis in patients with cervical squamous cell carcinoma,” Medical Science Monitor: International Medical Journal of Experi… [cited by applicant]
Yeh et al., “Wnt antagonists target porcupine and Axin,” Nature Chemical Biology, Feb. 2009, 5(2):74-5. [cited by applicant]
Yoshikawa et al., “Transcriptional analysis of hair follicle-derived keratinocytes from donors with atopic dermatitis reveals enhanced induction of IL32 gene by IFN-γ,” International Journal of Molecular Sciences, Feb. … [cited by applicant]
Zhang et al., “Tikil is required for head formation via Wnt cleavage-oxidation and inactivation,” Cell, Jun. 22, 2012, 149(7):1565-77. [cited by applicant]