Conference Proceeding | Published:

The insulin-like growth factor-I receptor and its role in thyroid-associated ophthalmopathy

Eyevolume 33pages200205 (2019) | Download Citation

Abstract

Background/objectives

Thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves’ disease, remains a disfiguring and potentially blinding condition. Here, the author reviews the role of insulin-like growth factor-I receptor pathway in TAO and how it might be therapeutically targeted.

Methods

The recent literature is reviewed.

Results

TAO involves reactivity of orbital connective tissues and their remodeling. While many of the details concerning the pathogenesis of TAO remain to be determined, several insights have come to light recently. Among them is the apparent involvement of IGF-IR. This receptor protein, a membrane-spanning tyrosine kinase receptor can form both physical and functional complexes with the thyrotropin receptor (TSHR). This is notable because TSHR is the established primary autoantigen in Graves’ disease. IGF-IR activity is critical to signaling downstream from both IGF-IR and TSHR. In addition, antibodies against IGF-IR have been detected in patients with Graves’ disease and in rodent models of TAO. Evidence has been put forward that these antibodies may act directly on IGF-IR, perhaps in some manner activating the receptor. These experimental observations have led to the development of a novel therapy for active TAO, utilizing a monoclonal anti-IGF-IR inhibitory antibody which had been produced originally as treatment for cancer. The agent, teprotumumab was recently evaluated in a clinical trial and found to be highly effective and relatively well-tolerated. It is currently undergoing assessment in a follow-up trial.

Conclusions

Should the current study yield similarly encouraging results, it is possible that teprotumumab will emerge as a paradigm-shifting medical therapy for TAO.

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Acknowledgements

These studies were supported in part by grant EY08976 from the National Institutes of Health and Core Center for Research grant EY007003 from the National Eye Institute. The author is grateful to Leslie Bordine for her expert assistance in the preparation of this manuscript.

Author information

Affiliations

  1. Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, 48105, USA

    • Terry J. Smith
  2. Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48105, USA

    • Terry J. Smith

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Conflict of interest

The author has been issued patents covering his invention of using IGF-I receptor inhibition as a therapy for Graves’ disease, TAO, and other autoimmune diseases. These are held by the Los Angeles Biomedical Institute and the UCLA School of Medicine.

Corresponding author

Correspondence to Terry J. Smith.

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DOI

https://doi.org/10.1038/s41433-018-0265-2