# SLE Treatment with N-acetylcysteine

> **NIH NIH U01** · UPSTATE MEDICAL UNIVERSITY · 2021 · $1,386,367

## Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology with mortality still
approaching 10% in 5 years. The leading cause of death in SLE are infections due to the toxicity of
immunosuppressant medications. Therefore, a significant unmet need exists for effective and non-toxic
medications to treat SLE. Our central hypothesis has been formulated on the basis that effective treatment
should target key checkpoints of pathogenesis, such as the depletion of reduced glutathione (GSH), which
underlies the activation of the mechanistic target of rapamycin (mTOR) and inflammatory lineage specification
of T cells, B-cell activation and antinuclear autoantibody production in SLE. The rationale for this study is
supported by evidence that 1) GSH is depleted in peripheral blood lymphocytes (PBL) of SLE patients; 2) GSH
depletion contributes to mTOR activation that drives T-cell dysfunction in SLE; 3) administration of N-
acetylcysteine (NAC), which serves as a cell-permeable amino acid precursor of GSH, blocks the development
of murine lupus; and 4) the preliminary studies suggest that NAC is safe, reverses GSH depletion and mTOR
activation and improves disease activity in SLE patients. In our completed double-blind placebo-controlled pilot
study, NAC was tolerated by 100% of patients on 1.2 g/day and 2.4 g/day dosages, while 33% of those
receiving 4.8 g/day had reversible nausea. Placebo and 1.2 g/day NAC did not influence disease activity.
Although both 2.4 g/day and 4.8 g/day NAC dosages showed preliminary evidence for clinical efficacy, 4.8
g/day NAC achieved greater drops in SLEDAI and BILAG scores. NAC raised GSH, blocked mTOR, and
expanded T regs. The proposed phase II trial will employ the SLE Responder Index (SRI), as a clinically
meaningful primary outcome measure that provides easily interpretable results and yields a feasible sample
size that is associated with adequate power to detect therapeutic benefit over 1 year. To minimize potential
intolerance of NAC and subject withdrawal, the study design includes an open-label dosage titration period.
Patients who tolerate 2.4-4.8 g daily NAC for 3 months will be randomly assigned 1:1 to continue treatment on
their tolerated dosage of NAC or matching placebo for 9 additional months. Beyond the premise of validating
clinical efficacy and durability of this therapy in SLE, the proposed studies will test the hypothesis that depletion
of GSH and cysteine and activation of mTOR predict immunobiological and clinical responsiveness to NAC.
The proposed studies will significantly advance our understanding of immune-metabolic pathways that control
T-cell lineage specification with translational relevance for the pathogenesis and treatment of lupus. The
approach is innovative as it will employ a safe therapeutic intervention to define the role of cysteine depletion in
redox-dependent mTOR activation and pro-inflammatory T-cell development in lupus patients in vivo. The
results will bring ...

## Key facts

- **NIH application ID:** 10188441
- **Project number:** 5U01AR076092-02
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Michael P McDermott
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,386,367
- **Award type:** 5
- **Project period:** 2020-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188441

## Citation

> US National Institutes of Health, RePORTER application 10188441, SLE Treatment with N-acetylcysteine (5U01AR076092-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10188441. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*