Genetic profiling of SLE patients with impaired NET degradation.

ABSTRACT Systemic Lupus Erythematous (SLE) is the most common form of lupus, accounting for approximately 70% of all lupus cases. Patients can present with a multitude of clinical manifestations and with a diverse range of serological biomarkers making diagnosis and therapy challenging. All current SLE therapies rely on immunosuppressive drugs for managing disease symptoms. Neutrolis’ founding team has deep understanding on the role of Neutrophil Extracellular Traps (NETs) in inflammatory and autoimmune conditions. NETs are extracellular lattices of intact chromatin filaments decorated with toxic proteins. We and others, have demonstrated that NETs bind autoantibodies and from pathological immune complexes in SLE. More recently, we could identify the molecular mechanism how NETs are degraded in vivo. At Neutrolis, we develop biologics that promote NET degradation and provide a non-immunosuppressive for the treatment of autoimmune and inflammatory diseases, including SLE. We have identified a lead candidate, a Chromatinase™ that eliminates the pathologic effects of NETs in animal models for acute diseases and SLE. In this research proposal, we aim to characterize genetic mutations that cause reduced NET degradation in SLE patients with the goal to identify and stratify patients who will benefit from the innovative Chromatinase™ therapy. Novel mutations will also be explored and tested from 100 samples of SLE patients. Results from this project will enable us to move forward to a SBIR Phase II, in which we will analyze additional 1,500 SLE patients to generate a comprehensive panel of genetic markers, which promotes the development of Chromatinase™ towards clinical trials. The collected and tested data will support Neutrolis clinical program for SLE and other autoimmune indications. Taken together, we at Neutrolis have the expertise, platform, innovation and capabilities to execute the proposed project successfully in a timely manner and when completed the product could be clinically important.NARRATIVE Neutrophil Extracellular Traps (NETs) are lattices of chromatin strands that contribute to the pathogenesis of systemic lupus erythematosus (SLE). Neutrolis is developing a lead candidate, a Chromatinase™, which provides non-immunosuppressive therapy against NETs for the treatment of SLE and other autoimmune diseases. In this project, Neutrolis proposes to characterize genetic mutations that cause impaired NET degradation in SLE and thus identify patients that are eligible for Chromatinase™ therapy.