- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Journal: Topical Vitamin D Receptor Antagonist/Partial-Agonist Treatment Induces Epidermal Hyperproliferation via RARγ Signaling Pathways. (Pubmed Central) - Nov 4, 2021
In this study we topically treated shaved mouse skin with a vitamin D agonist (MC903) or vitamin D antagonist/partial agonist (ZK159222) and compared the changes with acetone (control treatment) treatment for 14 days...Clustering the altered genes revealed that heparin-binding epidermal growth factor-like growth factor, the main driver of epidermal hyperproliferation, was increased via RARγ-mediated pathways, while other clusters of genes were mainly decreased which were comparable to the changes seen upon activation of the RARα-mediated pathways. In summary, we conclude that epidermal hyperproliferation of mouse skin in response to a topically administered vitamin D receptor antagonist/partial agonist (ZK159222) is induced via increased retinoic acid synthesis, retinoic acid levels and increased RARγ-mediated pathways.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Journal: The CysLTR receptor mediates leukotriene C-driven acute and chronic itch. (Pubmed Central) - Oct 22, 2021
LTC-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine...CysLTR played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch...Collectively, our study reveals that LTC acts through CysLTR as its physiological receptor to induce itch, and CysLTR contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Journal: Privileged Quinolylnitrones for the Combined Therapy of Ischemic Stroke and Alzheimer's Disease. (Pubmed Central) - Sep 29, 2021
For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen-glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide Aβ, modeling toxic insults found among the effects of AD.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Preclinical, Journal: Dual function of Langerhans cells in skin TSLP-promoted Tfh cell differentiation in mouse atopic dermatitis. (Pubmed Central) - Sep 26, 2021
Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen-glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide Aβ, modeling toxic insults found among the effects of AD. Together, these studies revealed a dual functionality of LCs in TSLP-promoted Tfh and Th2 cell differentiation in AD pathogenesis.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
[VIRTUAL] Topical application of house dust mite extract induces atopic dermatitis like symptoms in MiR146a/b-/-mice () - Sep 21, 2021 - Abstract #ESDR2021ESDR_440;
Previously, miR-146a-deficient mice have been shown to develop stronger skin inflammation in a mouse model of AD induced by vitamin 3D analogue MC903...The mRNA expression analysis showed that HDM treatment prompted the expression of Th2 related cytokines (IL-4 and IL13) and IL-6 in MiR146a/b-/- mice but no significant changes in wt mice. In conclusion, we have established a novel HDM-induced mouse model of AD, with stronger immune responses in MiR146a/b-/- mice.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Preclinical, Journal: Cutaneous Effects of In Utero and Lactational Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin. (Pubmed Central) - Aug 27, 2021
The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical...These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Journal: IL-37 Targets TSLP-Primed Basophils to Alleviate Atopic Dermatitis. (Pubmed Central) - Aug 12, 2021
We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37...In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Clinical, Journal: Prospective pilot trial of calcipotriene as a novel topical treatment for acute skin graft versus host disease. (Pubmed Central) - Jul 2, 2021
We report the first prospective pilot study evaluating the topical vitamin D3 analog Calcipotriene (DOVONEX 0.005% cream) for acute skin GVHD in children, with associated analyses of target organ chemokine CXCL10 changes in response to therapy...In addition, we documented reduction of CXCL10 levels in the skin of seven subjects with GVHD after Calcipotriene course using non-invasive D-Squame® disc application to the skin for chemokine analysis. Our pilot study shows promising observation that topical Calcipotriene could be a novel therapeutic option for acute skin GVHD, especially in patients presenting with pruritus and should be studied in larger prospective studies.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Journal: Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. (Pubmed Central) - Jun 24, 2021
Analyses of cellular scratch assays and the MC903 mouse model of AD suggested that production of sphingolipids by R. mucosa, cholinergic signaling, and flagellin expression may have contributed to therapeutic impact through induction of a TNFR2-mediated epithelial-to-mesenchymal transition. These results suggest that a randomized, placebo-controlled trial of R. mucosa treatment in individuals with AD is warranted and implicate commensals in the maintenance of the skin epithelial barrier.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Engineered Herpes Simplex Virus Type 1 (HSV-1)-Based Vectors as a Platform for Localized Delivery of Therapeutic Antibodies in the Treatment of Skin Disorders () - Apr 30, 2021 - Abstract #ASGCT2021ASGCT_822;
P1/2, P3
(Krystal) has leveraged its HSV-1-based STAR-D (Skin-Targeted Delivery) platform to deliver therapeutic transgenes to patients with debilitating diseases, including vectors beremagene geperpavec (“B-VEC”) - encoding human COL7A1 for the treatment of dystrophic epidermolysis bullosa (ClinicalTrials.gov Identifier: NCT04491604), and KB105 - encoding human TGM1 for the treatment of autosomal recessive congenital ichthyosis (Clinicaltrials.gov Identifier: NCT04047732)...To evaluate the ability of a vector-encoded antibody to reduce an AD-like phenotype on a macro-scale, KB502 was applied topically in an MC903-induced murine model of AD...At this time, Krystal has expanded its STAR-D-based antibody portfolio to at least 12 unique products, including vectors expressing anti-CD20, anti-IL-17, and anti-CCR4 antibodies. The studies described herein warrant the further investigation of STAR-D as a platform for localized delivery of therapeutic antibodies, including for the treatment of diseases of skin and other organ systems amenable to immunomodulatory therapeutics.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
Journal: Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch. (Pubmed Central) - Apr 28, 2021
Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
NARROWBAND ULTRAVIOLET-B IRRADIATION AMELIORATES ATOPIC DERMATITIS BY MODULATING KERATINOCYTES VIA ARYL HYDROCARBON RECEPTOR () - Apr 23, 2021 - Abstract #ISAD2021ISAD_169;
MC903-induced AD-like lesions in mouse model were treated with NB-UVB irradiation (60 mJ/cm2 ), both clinical severity scores and histological presentation of skin lesions were evaluated...The expression of type 2 cytokine IL-13 and T cell activation marker OX40L in skin draining lymph nodes also decreased after NB-UVB irradiation. In conclusion, NB-UVB irradiation at therapeutic dose may up-regulate the expression of barrier protein via AHR pathway activation, and down-regulate the expression of epidermal proinflammatory cytokines TSLP in keratinocytes, which might be one of the mechanisms of NB-UVB treatment for AD.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
Journal: IL-37 Ameliorating Allergic Inflammation in Atopic Dermatitis Through Regulating Microbiota and AMPK-mTOR Signaling Pathway-Modulated Autophagy Mechanism. (Pubmed Central) - Mar 18, 2021
In vitro co-culture of human eosinophils and dermal fibroblasts upon AD-related IL-31 and IL-33 stimulation, and in vivo MC903-induced AD murine model were employed to investigate the anti-inflammatory mechanism of IL-1 family cytokine IL-37 in AD...In summary, IL-37b could significantly ameliorate eosinophils-mediated allergic inflammation via the regulation of autophagy mechanism, intestinal bacterial diversity and their metabolites in AD. Results therefore suggest that IL-37 is a potential anti-inflammatory cytokine for AD treatment.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
[VIRTUAL] AGE-ASSOCIATED DECLINE IN ESOPHAGEAL EPITHELIAL AUTOPHAGY FLUX MAY PROMOTE TISSUE REMODELING IN EOSINOPHILIC ESOPHAGITIS (DDW Virtual) - Mar 15, 2021 - Abstract #DDW2021DDW_1184;
Diminished autophagy flux occurring during esophageal tissue aging may impact EoE disease presentation by altering epithelial basal cell dynamics and cross-talk between esophageal epithelial cells and underlying stromal cells. Given that epithelial autophagy may influence EoE through cell intrinsic and cell extrinsic mechanisms, future efforts will explore strategies to activate autophagy flux in order to prevent or limit EoE-associated tissue remodeling events, including fibrosis and strictures.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
Journal: Critical Role of TSLP Receptor on CD4 T Cells for Exacerbation of Skin Inflammation. (Pubmed Central) - Mar 12, 2021
Similar results were obtained in Th2-type allergic skin inflammation model using MC903. Collectively, these results indicate that TSLP acts directly on CD4 T cells to elicit pathogenesis of Th2 cells, thereby having a critical role in exacerbation of skin inflammation in the chronic phase.
- |||||||||| Zyclara (imiquimod) / Mochida, Mylan, Bausch Health, Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Targeting of HDAC8 and HDAC9 in keratinocytes to enhance skin immune defense () - Feb 12, 2021 - Abstract #SID2021SID_207;
Topical treatment of mice with butyrate upregulated antimicrobial peptide production (Camp and mBD4) and subsequently inhibited S. aureus in mice despite elevated Th2 cytokines generated in an MC903-induced AD mouse model. These observations show a novel approach to enhance host defense against pathogens on human skin.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Role of voltage-gated T-type calcium channel in acute and chronic itch () - Feb 12, 2021 - Abstract #SID2021SID_147;
Pharmacological inhibition of T-type channels also significantly attenuated itch-evoked scratching in the MC903 mouse model of atopic dermatitis. Together, we demonstrate that T-type calcium channel plays an important role in acute and chronic itch.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Involucrin deficiency results in decreased vitamin D receptor-mediated inflammation and Csnk1e isoform bias (Meeting Platform) - Feb 12, 2021 - Abstract #SID2021SID_114;
We investigated the inflammatory responses in adult mice using the MC903 (vitamin D agonist) inducible model for atopic dermatitis...DEXseq analysis identified a bias for Csnk1e alternative transcripts in Ivl-/- mice. Together our findings reveal a functional role for the evolutionarily selected involucrin to regulate VDR-mediated inflammation and potentially for the circadian response in the skin.
- |||||||||| Dovonex (calcipotriol) / LEO Pharma, Novartis
Enrollment status, Trial completion date, Trial primary completion date: Efficacy and Safety of AD-MSCs Plus Calpocitriol Ointment and PSORI-CM01 Granule in Psoriasis Patients (clinicaltrials.gov) - Feb 8, 2021
P=N/A, N=8, Enrolling by invitation,
Together our findings reveal a functional role for the evolutionarily selected involucrin to regulate VDR-mediated inflammation and potentially for the circadian response in the skin. Recruiting --> Enrolling by invitation | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Jul 2020
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis, MOR106 / MorphoSys, Galapagos, Novartis
Journal: IL-17C amplifies epithelial inflammation in human psoriasis and atopic eczema. (Pubmed Central) - Jan 30, 2021
Recruiting --> Enrolling by invitation | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> Jul 2020 IL-17C amplifies epithelial inflammation in Th2 and Th17 dominated skin inflammation and represents a promising target for the treatment of ISD.
- |||||||||| [VIRTUAL] AHR agonist RLV102 suppresses inflammation in mouse models of eczema and psoriasis () - Jul 1, 2020 - Abstract #SID2020SID_515;
In imiquimod induced psoriasis model and MC903 induced atopic dermatitis model, RLV102 significantly inhibited development of skin inflammation at concentrations as low as 0.1% when applied topically. The results reported revealed that RLV102 is a novel AHR agonist with therapeutic potential for treatment of chronic inflammatory skin diseases such as psoriasis and eczema.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Involucrin knockout mice exhibit decreased Vitamin D receptor expression and reduced Vitamin D agonist-induced skin inflammation () - Jul 1, 2020 - Abstract #SID2020SID_177;
To test this hypothesis, we examined the inflammatory response in ear skins of Ivl -/- and control wild-type mice upon vitamin D agonist (MC903, calcipotriol) treatment...The data suggests a positive correlation for Ivl dosage to Vdr expressions that was further confirmed in primary human keratinocytes whereby darker pigmentation coincides with lower IVL and VDR. Together, our findings identify functional significance for IVL in the epidermis revealing an emerging paradigm for IVL dosage that has recently evolved in human adaptation to potentially regulate VDR expression in the epidermis.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Engineering the skin with microneedle arrays to induce immune tolerance () - Jul 1, 2020 - Abstract #SID2020SID_103;
Finally, tolerization or desensitization of mice with antigen+MC903 MNAs reduced subsequent hypersensitivity responses at distal sites in an antigen-specific manner, and significantly enhanced the ratio of regulatory to effector T cells in skin draining lymph nodes. These results suggest simultaneous introduction of antigen and tolerogen into the skin with MNAs can promote systemic antigen-specific tolerance, which may have broad implications for inflammatory disorders, autoimmunity, or transplantation.
- |||||||||| Zyclara (imiquimod) / Mochida, Mylan, Bausch Health, Vesimune (imiquimod) / UroGen, Dovonex (calcipotriol) / Leo Pharma, Novartis
[VIRTUAL] Enhancement of Th2 cell differentiation by TRIM32 deficiency is negatively associated with PKCζ () - Jul 1, 2020 - Abstract #SID2020SID_57;
In our previous studies, we showed that Trim32 null mice developed Th2 biased skin inflammation in response to imiquimod and associated low level of TRIM32 with AD...Furthermore, Prkcz null mice showed compromised AD-like phenotypes in the MC903 AD model...Taken together, these findings suggest that TRIM32 functions as a regulator of PKCζ that controls the differentiation of Th2 cells important for AD pathogenesis. Because TRIM32 is an E3 ubiquitin ligase with innate antiviral activity, Th2 regulation by TRIM32 provides a potential connection between defective innate immunity and Th2 activation in AD pathogenesis.
- |||||||||| Xolair (omalizumab) / Roche, Novartis
[VIRTUAL] Disruptive anti-IgE inhibitors for the treatment of allergic lung inflammation () - May 19, 2020 - Abstract #EAACI2020EAACI_570;
We established an adjuvant free allergic lung inflammation model in humanized huIg/huFcRI+/+mice. This experimental setup allows and facilitates the in vivo assessment of novel anti-human IgE drug candidates, such as disruptive anti-human IgE inhibitors.
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
The role of Thymic Stromal Lymphopoietin (TSLP) in protection from Type II diabetes (Board Number: P235) - Apr 25, 2020 - Abstract #IMMUNOLOGY2020IMMUNOLOGY_180;
Importantly, there was a robust increase in Tregs and decrease in CD8 T cells and NK cells in the adipose of MC903 and TSLP-treated mice. Together, our results suggest that activation of TSLP signaling may be a therapeutic immunotarget for improving insulin sensitivity and preventing Type II diabetes.
- |||||||||| Journal: Drugs for psoriasis. (Pubmed Central) - Nov 13, 2019
As esophageal epithelium is the first line of defense against ingested food allergens, future studies will define the precise molecular mechanisms through which mitochondrial dysfunction limits SCD with the goal of developing novel therapeutic strategies to restore barrier function in EoE. No abstract available
- |||||||||| Dovonex (calcipotriol) / Leo Pharma, Novartis
Journal: Eosinophils determine dermal thickening and water loss in a MC903 model of atopic dermatitis. (Pubmed Central) - Sep 14, 2019
Indeed, eosinophil depletion significantly ameliorated AD pathology, most notably barrier dysfunction, to a similar extent as blocking of the IL-4/IL-13 axis by genetic deletion of STAT6. Thus, this study has identified eosinophils to be critical for the development and maintenance of AD, thereby proposing these effector cells as therapeutic targets for the treatment of AD.
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