Graves’ disease is an autoimmune thyroid disorder that causes hyperthyroidism. Graves’ disease is directly caused by stimulating TSH receptor antibodies (also known as thyroid stimulating immunoglobulins or TSI) that order thyroid cells to produce excess hormone. TSI antibodies are also involved in the orbital and dermal manifestations of Graves’ disease.
Current Treatments
Current treatments for Graves’ disease either aim at destroying a perfectly normal organ that’s being targeted by a faulty immune system through radiation or surgery or with medications aimed at eliciting remission. These medications, which are known as anti-thyroid drugs (ATDs) are the most common treatment worldwide, but they’re often used incorrectly or not used to their potential. Furthermore, they can take several years to work and require monitoring of thyroid function with blood tests. Used appropriately, that is, using the lowest dose needed until remission is confirmed, they work well. However, this isn’t often the case, which leads to relapses and recommendations for thyroid gland destruction.
The Novel Molecule
At last, researchers are investigating the cause of Graves’ disease and looking for therapies aimed at stopping the disease process. Because TSI antibodies cause hyperthyroidism, anti-thyroid drug therapies bring patients into remission by both lowering thyroid hormone levels and reducing TSI antibody production. However, ATD therapy is often stopped before TSI antibody reduction is adequate and the immune system healed. Often, as soon as thyroid hormone levels are corrected, the medications are prematurely stopped.
The novel molecule making headlines is a small-molecule antagonist that directly inhibits or prevents TSI from activating the TSH receptor. The TSH receptor is a protein lock that’s found on thyroid, pituitary, skin, orbital, musculoskeletal, and other cells in the body. When TSI activates the TSH receptor on thyroid cells, the cells are ordered to produce excess thyroid hormone. Blocked by the novel molecule, TSI doesn’t cause hyperthyroidism. TSI also contribute to the development of Graves’ ophthalmopathy (thyroid eye disease) when these antibodies activate TSH receptors on orbital cells; and they contribute to pretibial myxedema when they activate the TSH receptor on dermal cells. This novel antagonist molecules offers great promises for these disorders as well.
The Study
Dr. Marvin Gershengorn and Susanne Neumann and their teams at the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases and National Institutes of Health Chemical Genomics Centers at the National Institutes of Health have isolated this molecule and they’ve shown that it inhibits receptor signaling. This was demonstrated in four patients with active Graves’ disease using in vitro systems.
The researchers have investigated several analogs of the small-molecule and are currently working with the best molecule for human study. In this model system, NCGC00229600 inhibited both basal and TSH-stimulated cAMP production although TSH binding was not affected.
The small-molecule antagonist has not yet been studied in clinical trials. Further research in patients with both Graves’ disease and Graves’ ophthalmopathy is expected to begin in the near future. In addition, the researchers are studying other effects of this antagonist on thyroid regulation. By researching the thyroid-stimulating hormone receptor, they're hoping to use drug-like compounds such as the small-molecule antagonist to stimulate this receptor in patients with thyroid cancer. The idea is that these individuals could receive greater stimulation of thyroid cancer cells, which would presumably increase the efficacy of iodine radiation. A small molecule capable of stimulating the TSH receptor has already been tested in animal trials
Reference:
Susanne Neumann, Elena Eliseeva, Joshua McCoy, et. al., 2011. A New Small-Molecule Antagonist Inhibits Graves’ Disease Antibody Activation of the TSH Receptor. The Journal of Clinical Endocrinology and Metabolism; 96(2): 548-554.
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