PROJECT SUMMARY/ABSTRACT
Vitiligo is characterized by the patchy loss of skin pigmentation that can adversely affect a person’s quality of life
and sense of well-being. Despite the prevalence of vitiligo [over 2 million U.S. citizens are affected by vitiligo and
the global cases range from 0.5% to 2% of the population], there is only one FDA-approved therapeutic for
vitiligo; a topical formulation of the Janus kinase (JAK)-inhibitor sold under the trade name Opzelura. Significant
shortcomings of Opzelura include: the limited response rate and the high cost. Thus, there is a critical need for
the development of novel therapeutics for vitiligo. The long-term research goal of this project is to discover and
develop safe and cost effective small organic compounds that can be used as therapeutics for vitiligo.
Investigations into the autoimmune mechanisms of vitiligo have revealed: (i) high levels of expression of the
cytokine CXCL10 at active sites of vitiligo in murine and human tissue; (ii) that inhibition of interferon-gamma
(IFN-γ) signaling, which induces CXCL10 expression, is protective from vitiligo in a murine model; and (iii) that
neutralization of CXCL10 can induce reversal of the disease in a murine model. These observations have led to
the conjecture that reagents which inhibit IFN-γ induced CXCL10 expression by keratinocytes, the main source
of CXCL10, could be developed into therapeutics for vitiligo.
The research team has identified a family of highly potent and specific inhibitors of glycogen synthase kinase-3
(GSK-3). The team recently discovered that COB-187, the lead compound within this family, inhibits IFN-γ
induced CXCL10 expression by human keratinocytes. These observations have led us to the following central
hypothesis: COB-187 is efficacious in vitiligo. To investigate this hypothesis, the following aims will be completed:
(i) to determine the ability of COB-187 to attenuate IFN-γ induced cytokine expression by human keratinocytes;
and (ii) to determine the mechanism by which COB-187 inhibits IFN-γ induced CXCL10 expression by
keratinocytes.
The family of compounds exemplified by COB-187 have the potential to become therapeutics for vitiligo. The
proposed work will provide a strong scientific foundation for the development of such therapeutics. Thus,
successful completion of these studies will have a positive impact on the large number of people who suffer from
vitiligo.
Public Health Relevance Statement
PROJECT NARRATIVE
Vitiligo, which is characterized by the patchy loss of skin pigmentation, affects over 2 million U.S. citizens and
between 0.5% to 2% of the global population. Despite the large number of people adversely affected by this
condition, therapeutic options for vitiligo are quite limited. Thus, this work seeks to develop a novel small
molecule therapeutic for vitiligo.
NIH Spending Category
No NIH Spending Category available.
Project Terms
Active SitesAffectAntibodiesApoptosisAttenuatedAutoimmune ProcessBindingBiological AssayCXCL10 geneCXCL9 geneCXCR3 geneCell CycleCell NucleusCell SurvivalCreamDataDevelopmentDiseaseDrug KineticsEpidermisFDA approvedFamilyFormulationFoundationsFutureGlycogen (Starch) SynthaseGlycogen Synthase Kinase 3GoalsHumanInterferon Type IIInvestigationJanus kinaseLeadMaintenanceMetabolicMotivationMusNamesOhioPatientsPersonsPharmaceutical PreparationsPharmacodynamicsPhasePhosphorylationPopulationPrevalenceProliferatingQuality of lifeReagentResearchRoleSamplingSignal TransductionSkinSkin PigmentationSmall Business Technology Transfer ResearchSourceTestingTherapeuticTubeUniversitiesVitiligoWell in selfWorkautoimmune pathogenesisbeta cateninchemokinecostcost effectivecytokineexpectationhuman modelhuman tissueinhibitorinsightkeratinocytekinase inhibitormelanocytemouse modelnovelnovel therapeuticsphase 2 studypreventresponsesafety studysmall molecule therapeutics
National Institute of Arthritis and Musculoskeletal and Skin Diseases
CFDA Code
846
DUNS Number
UEI
SJCYNKY7KJ36
Project Start Date
10-September-2024
Project End Date
31-August-2025
Budget Start Date
10-September-2024
Budget End Date
31-August-2025
Project Funding Information for 2024
Total Funding
$306,278
Direct Costs
$263,866
Indirect Costs
$22,375
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Arthritis and Musculoskeletal and Skin Diseases
$306,278
Year
Funding IC
FY Total Cost by IC
Sub Projects
No Sub Projects information available for 1R41AR084965-01
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