DNA is a foundational biologic molecule and the carrier of genetic information. However, the study of NETs has revealed the dark side of DNA. DNA released into the extracellular space is a key trigger of numerous previously unrecognized pathological functions.
When NETs formation overwhelms natural clearance mechanisms, NETs accumulate and trigger a number of pathological mechanisms including autoimmunity, inflammation, thrombosis and tumor metastasis at the root of several chronic and acute diseases.
DNA is a foundational biologic molecule and the carrier of genetic information. However, the study of NETs has led to the discovery of the dark side of DNA. Extracellular DNA is a key trigger of numerous previously unrecognized pathological functions.
When NETs formation overwhelms natural clearance mechanisms, NETs accumulate and trigger a number of pathological mechanisms including autoimmunity, inflammation, thrombosis and tumor metastasis at the root of several chronic and acute diseases.
Neutrophils are the most abundant immune cells in the human body. They are a critical component of the innate immune system and respond to several stimuli, including immune activation and infectious disease.
When triggered, neutrophils can expel their long chromatin fibers to form NETs. NETs are an ancient part of the innate immune system and are believed to have evolved as an antibacterial defense mechanism to create a "bio-bandage" around wounds. In humans, NETs deployed in the wrong place for too long are a root cause of several major diseases.
Once extruded, NETs become a key binding substrate for anti-DNA autoantibodies, which have been characterized in autoimmune patients for decades. NETs are a large macromolecular assemblage made up of nucleosomes — the unpacked DNA bound to the thousands of histone proteins that comprise chromatin. Because each anti-DNA autoantibody can bind to a single nucleosome, NETs can sequester millions of distinct autoantibodies. This drives the formation of immune complexes and leads to harmful disease flares in conditions such as lupus.
The exDNASE™ platform powers the design, rapid prototyping and manufacturing of DNASE enzyme analogs of naturally occurring enzymes. Molecules produced by the platform are designed with enhanced ability to disassemble NETs and optimized for therapeutic properties. Previous NETs treatment strategies have predominantly focused on inhibiting NETs formation and have not led to clinically effective anti-NET treatments.
Upon administration of Neutrolis’ therapies, NETs are immediately disassembled into nucleosomes to attenuate their pathological function.
Once NETs are disassembled into nucleosomes, there is a million-fold reduction in size of the NETs complex and flare-triggering properties are eliminated. The nucleosome byproducts are of uniform length and become soluble in blood, which make them helpful pharmacodynamic markers to guide the development and administration of Neutrolis' therapies.
Our proprietary exDNASE™ platform is based on the naturally selected enzymes that evolved to disassemble the extracellular chromatin that form NETs. The platform powers the design, rapid prototyping, selection and manufacturing of engineered enzyme analogs with enhanced ability to disassemble NETs and optimized for use in different therapeutic settings. Neutrolis’ lead program, NTR-L301, is being initially developed to address lupus.
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