Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 6

Targeting the mTOR Pathway for Treatment of Systemic Lupus Erythematosus

Andras Perl, M.D., Ph.D.
State University of New York at Syracuse

The cause of systemic lupus erythematosus (SLE) is unknown and current therapies have limited efficacy. A rational approach for therapeutic design requires a detailed understanding of disease pathogenesis. The mitochondria play crucial roles in T-cell activation and death, which are abnormal in patients with SLE; however, in altered lymphocyte activation and death of SLE patients, the mechanistic roles of mitochondria and the underlying metabolic pathways are unknown. Our preliminary studies identified mitochondrial dysfunction in lupus T cells which is characterized by persistent mitochondrial hyperpolarization (MHP) and consequential ATP depletion, resulting in decrease of activation-induced apoptosis and predisposition of T cells for necrosis, which stimulates inflammation in SLE. We also found persistent MHP to be associated with increased mitochondrial mass and increased mitochondrial and cytoplasmic Ca²⁺ content and enhanced Ca²⁺ fluxing in lupus T cells. The mammalian target of rapamycin or mTOR is a large protein kinase that is associated with the outer mitochondrial membrane and senses changes in the mitochondrial transmembrane potential of T cells. Rapamycin (sirolimus, Rapamune), a lipophilic macrolide antibiotic has improved the outcome of murine lupus and has been used to treat renal transplant rejection since 1999. With a focus on mitochondrial dysfunction, we utilized rapamycin for treatment of nine SLE patients resistant or intolerant to conventional medications. A single 2mg daily oral dose of rapamycin markedly reduced disease activity and prednisone use. In patients treated with rapamycin, we observed normalization of CD3/CD28-induced Ca²⁺ fluxing and of mTOR activity and persistence of MHP, indicating that 1) increased Ca²⁺ fluxing is downstream of MHP and 2) mTOR is a sensor and effector of MHP in lupus T cells. Rapamycin can selective expand CD4+/CD25+/Foxp3+ regulatory T cells (Tregs) which are deficient in patients with active SLE. These data clearly show that MHP and activation of the mTOR pathway are relevant for lupus pathogenesis. Future studies will examine the mechanism of mTOR activation and its impact on Ca²⁺ fluxing and the expansion of Tregs in SLE.

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