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ATI-1777 a topical JAK1/3 inhibitor may benefit atopic dermatitis without systemic drug exposure, results from preclinical development and Phase 2a randomized-control study ATI-1777-AD-201

ABSTRACT: Atopic dermatitis (AD), a chronic, pruritic skin disease, affects 10%-30% of children and up to 14% of adults in developed countries. Since current AD treatments may lead to systemic drug exposure and AD pathophysiology is partially mediated by JAK1/3 signaling, ATI-1777, a potent and selective JAK1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited JAK1/3 with limited systemic exposure and without any adverse effects. ATI-1777-AD-201 (NCT04598269), a Phase 2a, first-in-human, randomized, double-blind,vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48participants with AD over 4 weeks. The primary outcome was reduction of a modified EASI score from baseline; reduction was significantly greater in the ATI-1777 group at Day28 compared to vehicle (percent reduction from baseline 74.45% [SE6.455] and 41.43% [SE6.189], respectively [p<0.001]). Average plasma concentrations of ATI-1777 were <5% of the IC50 of ATI-1777 for inhibiting JAK1/3. No deaths or serious adverse events were reported. This demonstrates that topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of AD.

ORGANISM(S): Sus scrofa

PROVIDER: GSE244201 | GEO | 2023/11/20

REPOSITORIES: GEO

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Project description:Wheat (Triticum aestivum ssp. aestivum) contributes to 20% of the human protein supply, delivers essential amino acids and is of fundamental importance for bread and pasta quality. Wheat proteins are also involved in adverse human reactions like celiac disease, wheat allergy and the non-celiac wheat sensitivity (NCWS). Using LC-MS-based LFQ proteomics of aqueous flour extracts we determined 756 proteins across 150 wheat varieties grown in three environments. However, only 303 proteins were stably expressed across all environments in at least one variety underlining the large influence of environmental conditions on the expression of many proteins. Moreover, only 89 proteins were comparably expressed by all 150 varieties, with high coefficients of variation for the other proteins. Heritability (h) ranged from 0-1 with 114 proteins having h² > 0.6. Therefore, the expression of the variable proteins should be amenable to targeted manipulation across the wheat supply chain by varietal choice and breeding. Our study provides a first approach towards a fast and high-throughput methodology for quantifying these proteins which is required to breed wheats with the desired properties. Amylase trypsin inhibitors (ATIs) appear as a potential trigger for NCWS inducing intestinal and extra-intestinal inflammation. Studies on the prevalence and genetic architecture of ATI proteins in wheat are lacking so far. Large differences in the content and composition of 8 ATIs in the different varieties were identified by QconCAT-assisted quantification. The ATI proteins had low coefficients of correlations with quality traits commonly analyzed in wheat breeding. However, heritability was quite low except for ATI 0.28 and ATI CM2. A genome wide association mapping revealed a complex genetic architecture built up on many small but few medium and two major quantitative trait loci (QTL). The latter were on chromosome 3B for ATI 0.19-like and 6B for ATI 0.28 explaining 70.6 and 68.7% of the genetic variance, respectively. Using the wheat reference genome sequence, seven potential candidate genes behind the medium and major QTL were described with only one showing polymorphism based on exome capture analysis. Consequently, wheat breeding could contribute to a reduction of ATI contents in wheat products if incidence of ATI on human health is further confirmed.

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ATI-1777 a topical JAK1/3 inhibitor may benefit atopic dermatitis without systemic drug exposure, results from preclinical development and Phase 2a randomized-control study ATI-1777-AD-201

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