Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease.

BACKGROUND

Thyroid eye disease (TED) is characterized by orbital inflammation and complicated by extraocular muscle fibrosis. Treatment with rapamycin/sirolimus has been reported to improve ocular motility and disease manifestations in TED. Whether this resulted from a primary antifibrotic effect on fibroblasts or was secondary to immune-suppression is unclear.

METHODS

In vitro contractility studies of primary orbital fibroblasts. Cells from patients with TED and controls were treated with rapamycin [mechanistic target of rapamycin an (mTOR) inhibitor] and MHY1485 (an mTOR stimulator) as well as inhibitors upstream in the same signaling cascade (saracatinib and befatinib).

RESULTS

At concentrations consistent with the therapeutic dosing range in humans, rapamycin/sirolimus significantly reduces fibrosis in orbital fibroblasts from TED patients and controls in vitro. This effect is separate from, and in addition to, its immune suppressive effect. mTOR-driven fibrotic activity is greater in TED-derived fibroblasts and can be blocked also upstream of mTOR by inhibition of src. There was no adverse effect on cell survival.

CONCLUSION

The authors present evidence for a direct antifibrotic effect of rapamycin/sirolimus in primary orbital fibroblasts. Targeting mTOR signaling presents a further and adjunctive treatment of TED alongside other immune-suppressive agents. By acting downstream of IGF1-R, sirolimus may offer a cost-effective alternative to teprotumumab therapy. Clinical case reports, now supplemented by this in vitro evidence, support the initiation of a clinical trial to treat the fibrotic sequelae of TED with this already-approved agent. Such an "off-the-shelf" therapy is a welcome prospect for TED treatment, particularly one available at a low price.