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Abstract: SA-OR30

Inhibition of Toll-Like Receptor 7 (TLR7) With a Selective Inhibitor of Human TLR7 ST-301 Reverse Lupus Progression in Murine Lupus Models

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Yu, Michael Z., Hillhouse Medical Group, Houston, Texas, United States
  • Lee, Helen, Hillhouse Medical Group, Houston, Texas, United States

Group or Team Name

  • Hillhouse Medical Group/Singularity Therapeutics INC
Background

Toll-like receptor 7 (TLR7) is an endosomal innate viral RNA sensor, primarily expressed in plasmacytoid dendritic cells and B cells. A large body of evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease.
Blocking the TLR7 pathway has been investigated in SLE disease models. ST-301 is a potent selective TLR7 inhibitor and has similar human and mouse potency. ST-301 was used to investigate the role of TLR7 signaling in murine lupus models

Methods

MRL/lpr and NZB/W mice were treated with a vehicle or a selected dose of ST-301, prednisolone, and ST-301 plus prednisone. MRL/lpr mice were treated for 6 weeks on the early-stage disease with positive anti-dsDNA antibodies but negative proteinuria. NZB/W mice were treated for 20 weeks on the early-stage disease with positive anti-dsDNA antibodies but negative proteinuria, twelve weeks on established disease (proteinuria <100 mg/dL), and eight weeks on advanced disease (proteinuria >100 mg/dL).

Results

Six weeks of treatment with ST-301 on the MRL/lpr early-disease mice provided a significant delay of proteinuria onset, reduction of autoantibody production, and inhibition of IgG deposition in the kidney. Twenty weeks of treatment with ST-301 on the NZB/W early-disease mice resulted in a significant delay in the onset of lupus nephritis, onset of proteinuria, reduction of serum IgG level, and IgG deposition in the kidney. Treatment of NZB/W mice with ST-301 on established disease mice for twelve weeks and advanced disease mice for eight weeks resulted in a reduction of proteinuria, kidney IgG deposition, interstitial fibrosis, and a significant increase in survival in both established and advanced disease mice models. Serum autoantibody levels were significantly reduced in early-stage, established, and advanced disease mice models.

Conclusion

The novel highly selective TLR7 inhibitor ST-301 displayed robust efficacy in delaying the onset of Lupus nephritis, progression of Lupus nephritis, and survival benefit on MRL/lpr and NZB/W Murine Lupus Models. ST-301 significantly reduces proteinuria, autoantibodies production, and immune complex deposition. Resulting in a significant decrease of kidney interstitial fibrosis in established and advanced disease mice models. These results support that inhibiting the TLR7 pathway is a potential treatment for SLE.

Funding

  • Commercial Support