Targeting pathogenic endothelial dysfunction in systemic lupus erythematosus: translation to clinical trials

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that causes kidney damage and increases the risk of illness, disability, and death. Current treatments mainly suppress the immune system but do not effectively prevent long-term damage to the kidneys and blood vessels. One key problem in LN is that the cells lining blood vessels, called endothelial cells, do not work properly due to reduced production of a molecule called nitric oxide and increased oxidative stress, both of which lead to inflammation and kidney injury and heart complications.

L-sepiapterin (PTC923 or Sephience™) is an FDA-approved oral drug that helps restore normal function in these blood vessel cells. In animal studies, PTC923 improved blood vessel function, increased survival, and reduced kidney inflammation and scarring. We have also identified blood markers that may show when blood vessels are not functioning properly and how well patients respond to treatment with PTC923 aimed at improving blood vessel function.

This project aims to translate these discoveries into human studies by completing regulatory requirements for drug development and clinical trials, validating these blood markers, and testing PTC923 in a small clinical trial of patients with LN and blood vessel dysfunction. We will measure how PTC923 affects both blood vessel health and levels these markers to determine if it can improve patient outcomes. This study will provide important information to decide whether to move forward with larger clinical trials.

PTC923 is provided by PTC Therapeutics, who supports this research by providing expertise and study drug. We will seek additional funding from government, foundations, and industry partners and work with experts to develop partnerships that help bring this treatment to patients. This innovative approach has the potential to improve kidney and blood vessel health in lupus in ways current therapies cannot.

Lupus nephritis (LN) is associated with higher morbidity and mortality in patients with systemic lupus erythematosus. Current immunosuppressive therapies inadequately address long-term renal and vascular complications, underscoring the urgent need for novel treatments targeting underlying pathogenic mechanisms. Endothelial dysfunction (ED), characterized by reduced nitric oxide (NO) bioavailability and oxidative stress due to oxidative uncoupling of endothelial nitric oxide synthase (eNOS), is a central driver of vascular and renal injury in SLE. Thus, targeting this stromal cell population that amplifies immune responses offers a novel strategy to improve outcomes. L-sepiapterin (L-Sep; Sephience; PTC923) is an FDA approved, orally bioavailable tetrahydrobiopterin (BH4) prodrug that restores eNOS coupling and NO production. Its advantage over previously studied BH4 is that it is not rapidly oxidized to its inactive form (BH2) in the circulation as BH4 itself is. Preclinical studies in an angiotensin II hypertension model demonstrated the PTC923 improved endothelial function despite the oxidative stress that occurs in this model. In a murine LN model, PTC923 improved survival, reduced renal inflammation, fibrosis, and tubule ferroptosis, and normalized endothelial and tubular epithelial cell gene expression. Companion biomarker development has identified circulating markers of risk for ED and oxidative stress that associate with SLE and hypertension. We have also identified biomarkers with promise to show therapeutic response to PTC that change with therapy in hypertension trials but have not been tested as biomarkers of response to ED therapy.

This proposal aims to bridge these findings into clinical translation by filling gaps in development not addressed by traditional funding mechanisms. We will conduct a rigorous, milestone-driven project focused on validating biomarkers and pharmacodynamic endpoints, completing regulatory approvals, and performing a proof-of-principle clinical trial of PTC923 in high-risk LN patients with documented ED. The study will assess PTC923’s dose-dependent effects on endothelial function (via EndoPAT reactive hyperemia index) and biomarker reflection of baseline ED and response to therapy. This project will provide critical data to support go/no go decisions on further clinical development and inform dosing in a larger clinical trial. This mechanistically targeted approach promises to redefine vascular and renal disease prevention in SLE, offering a novel therapeutic strategy with strong translational potential.

PTC923 (Sephience™) is owned by PTC Therapeutics, which has provided investigational drug support and is a committed partner for clinical development in LN. We will actively pursue federal grants, foundation funding, and industry partnerships to support advanced clinical trials. Ongoing discussions with commercial partners and venture capital entities aim to secure non-dilutive and venture funding. While no startup company has been formed, academic-industry collaborations, including with PTC Therapeutics and business development experts at the Zucker Institute, will be leveraged to accelerate licensing, partnership formation, and eventual commercialization, ensuring broad patient access upon successful clinical validation.