Selective Janus kinase 1 inhibition resolves inflammation and restores hair growth offering a viable treatment option for alopecia areata.

Autor: Mattsson J; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Israelsson E; Translational Science and Experimental Medicine Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Björhall K; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Yrlid LF; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Thörn K; Translational Science and Experimental Medicine Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Thorén A; Animal Science and Technologies Clinical Pharmacology & Safety Sciences BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Toledo EA; Animal Science and Technologies Clinical Pharmacology & Safety Sciences BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Jinton L; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Öberg L; Translational Science and Experimental Medicine Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Wingren C; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Tapani S; Early Biometrics & Statistical Innovation Data Science & AI BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Jackson SG; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Skogberg G; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Lundqvist AJ; Drug Metabolism & Pharmacokinetics Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Hendrickx R; Drug Metabolism & Pharmacokinetics Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Cavallin A; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Österlund T; The Discovery Sciences Unit BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Grimster NP; Chemistry Oncology R&D AstraZeneca Waltham Massachusetts USA., Nilsson M; Medicinal Chemistry BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden., Åstrand A; Bioscience, Research and Early Development Respiratory & Immunology (R&I) BioPharmaceuticals R&D AstraZeneca Gothenburg Sweden.
Jazyk: angličtina
Zdroj: Skin health and disease [Skin Health Dis] 2023 Jan 29; Vol. 3 (3), pp. e209. Date of Electronic Publication: 2023 Jan 29 (Print Publication: 2023).
DOI: 10.1002/ski2.209
Abstrakt: Background: Janus Kinase (JAK) inhibition has recently demonstrated therapeutic efficacy in both restoring hair growth and resolving inflammation in Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile.
Objectives: We explored the possibility to separate the beneficial and adverse effects of JAK inhibition by selectively inhibiting JAK1 and thereby avoiding side effects associated with JAK2 blockade.
Methods: The C3H/HeJ mouse model of AA was used to demonstrate therapeutic efficacy in vivo with different regimens of a selection of JAK inhibitors in regards to systemic versus local drug exposure. Human peripheral blood lymphocytes were stimulated in vitro to demonstrate translation to the human situation.
Results: We demonstrate that selective inhibition of JAK1 produces fast resolution of inflammation and complete restoration of hair growth in the C3H/HeJ mouse model of AA. Furthermore, we show that topical treatment does not restore hair growth and that treatment needs to be extended well beyond that of restored hair growth in order to reach treatment-free remission. For translatability to human disease, we show that cytokines involved in AA pathogenesis are similarly inhibited by selective JAK1 and pan-JAK inhibition in stimulated human peripheral lymphocytes and specifically in CD8 + T cells.
Conclusion: This study demonstrates that systemic exposure is required for efficacy in AA and we propose that a selective JAK1 inhibitor will offer a treatment option with a superior safety profile to pan-JAK inhibitors for these patients.
Competing Interests: All authors are or were at the time employed by AstraZeneca.
(© 2023 AstraZeneca. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)
Databáze: MEDLINE
Externí odkaz: