Linsitinib, an IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease.
Graves’ disease (GD)
IGF-1R
autoimmune disorder
inflammation
linsitinib
thyroid eye disease (TED)
Journal
Frontiers in endocrinology
ISSN: 1664-2392
Titre abrégé: Front Endocrinol (Lausanne)
Pays: Switzerland
ID NLM: 101555782
Informations de publication
Date de publication:
2023
2023
Historique:
received:
24
04
2023
accepted:
06
06
2023
medline:
13
7
2023
pubmed:
12
7
2023
entrez:
12
7
2023
Statut:
epublish
Résumé
Graves' disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED. Linsitinib was administered orally for four weeks with therapy initiating in either the early ("active") or the late ("chronic") phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H&E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify Linsitinib prevented autoimmune hyperthyroidism in the Here, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves' disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves' Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease.
Identifiants
pubmed: 37435490
doi: 10.3389/fendo.2023.1211473
pmc: PMC10331459
doi:
Substances chimiques
3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
0
Imidazoles
0
Protein Kinase Inhibitors
0
Receptor, IGF Type 1
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1211473Informations de copyright
Copyright © 2023 Gulbins, Horstmann, Daser, Flögel, Oeverhaus, Bechrakis, Banga, Keitsch, Wilker, Krause, Hammer, Spencer, Zeidan, Eckstein, Philipp and Görtz.
Déclaration de conflit d'intérêts
Authors AS and RZ were employed by the company Sling Therapeutics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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