ETA2023 45th Annual Meeting of the European Thyroid Association ETA 2023 Oral Session 9: Thyroid Eye Disease (5 abstracts)
Linsitinib, AN IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease
Anne Gulbins 1 , Mareike Horstmann 2 , Anke Daser 3 , Ulrich Flögel 4 , Michael Oeverhaus 5 , Nikolaos Bechrakis 6 , J Paul Banga 7 , Simone Keitsch 8 , Barbara Wilker 8 , Gerd Krause 9 , Gary Hammer 10 , Andy Spencer 11 , Ryan Zeidan 11 , Anja Eckstein 12 , Svenja Philipp 13 & Gina-Eva Görtz 14
1Molecular Ophthalmology, Department of Ophthalmology, Essen, Germany; 2Univerity Hospital Essen, Molecular Ophthalmology, Department of Ophthalmology, Essen, Germany; 3Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany, Department of Otolaryngology, Germany; 4Heinrich Heine University, Department of Molecular Cardiology, Germany; 5Universitätsklinikum Essen, Klinik für Augenheilkunde, Essen, Germany; 6Klinik für Augenheilkunde, Universitätsklinikum Essen, Department of Ophthalmology, Molecular Ophthalmology Group, University of Duisburg-Essen, Essen, Germany, Essen, Germany; 7King’s College London, Molecular Ophthalmology, Department of Ophthalmology, Diabetes and Endocrinology, London Se5 9nu, United Kingdom; 8Department of Molecular Biology, Germany; 9Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Structure Biology, Berlin, Germany; 10University of Michigan, Department of Internal Medicine, Endocrinology, Ann Arbor, MI, United States; 11Sling Therapeutics, United States; 12Univ.-Augenklinik, Department of Ophthalmology, University Eye Hospital Essen, Essen, Germany; 13Department of Ophthalmology, Molecular Ophthalmology, Essen, Germany; 14University Hospital Essen, Molecular Ophthalmology, Molecular Ophthalmology, Essen, Germany
Study objective: 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 Graves’ Disease and thyroid eye disease. Graves‘ disease (GD), also known as ‘Basedow’s disease‘, is the most common cause for hyperthyroidism, typically presenting in patients between 40-60 years. GD is an autoimmune condition of the thyroid which is 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 and occurs in about 50% of the clinical cases.
Methods: To induce Graves’ Disease in mice we immunized mice 3-times with a plasmid encoding for the A-subunit of the TSHR. During an early and late stage, resembling the active and chronic state of the autoimmune disease, linsitinib was administered orally for four weeks. Typical clinical features in thyroid eye disease and inflammation were determined by histology and MRI.
Results: As seen in the histology, linsitinib prevented autoimmune hyperthyroidism, morphological changes, formation of brown adipose tissue in the orbita and orbital immune cell infiltration into the orbit in the active state as well as the chronic phase. To evaluate the effect of linsitinib during the course of therapy, living mice were examined via MRI. A distinctive migration of immune cells in the orbit, visualized by F19 imaging, with consecutive inflammation can be seen in the TSHR-immunized group, which is completely blocked by treatment with linsitinib. In addition, the orbital inflammation was partnered with the onset of muscle edema and formation of brown adipose tissue in TSHR-immunized mice, effects that were abrogated upon application of linsitinib.
Conclusion: In summary, we demonstrate the development of GD and TED in a mouse model upon immunization against the TSHR. The IGF-1R antagonist linsitinib blocks the development of the local pathologies of GD and TED in an early and late phase of the autoimmune disorder and also prevents development of the autoimmune response. We show that treatment of immunized mice with linsitinib after disease onset significantly limited the severity of the disease, 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 first line treatment of thyroid eye disease.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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