Paroxysmal nocturnal hemoglobinuria (PNH) is a blood condition which is exceptionally uncommon and which poses serious risks to people's health. Protheragen employs a brilliant group of researchers and scientists that have rich experience with PNH. They are highly focused on devising new innovative treatments to PNH and endeavoring to fulfill particular therapeutic gaps while driving progress in therapeutics development.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare sidelined acquired disorder of hematopoietic stem cells, with complement-mediated hemolysis, thrombosis, and bone marrow failure. This arises from a somatic mutation of the PIGA gene leading to deficient glycosylphosphatidylinositol (GPI)-anchored proteins on blood cells. This causes red blood cells (RBCs) to be very sensitive to the onslaught of the complement system, causing chronic intravascular hemolysis and variousother complications.
Fig. 1 Pathogenesis of hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). (Gurnari, Carmelo, et al., 2021)
Understanding the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) is important for the development of therapies that target complement-mediated hemolysis to improve symptom relief and quality of life for individuals with this hematological disorder. The pathogenesis of PNH is most often due to somatic mutations of the PIGA gene.
PIGA Mutation
The PIGA gene encodes a key enzyme for the synthesis of glycosylphosphatidylinositol (GPI) anchors. PIGA mutations result in a deficiency of GPI-anchored proteins on the surface of blood cells, specifically CD55 and CD59, which protect red blood cells from complement-mediated destruction.
Complement System Dysregulation
Due to the lack of CD55 and CD59, uncontrolled complement cascade progression leads to excessive formation of the membrane attack complex (MAC), which lyses red blood cells and activates platelets and endothelial cells. This dysregulation also leads to chronic inflammation and thrombotic risk.
Intravascular Hemolysis
Uncontrolled complement attack on GPI-deficient red blood cells results in intravascular hemolysis with the release of hemoglobin directly into the bloodstream. This leads to hemoglobinuria, iron deficiency, and nitric oxide scavenging, which can lead to complications such as fatigue, dysphagia, and thrombosis.
The therapeutic landscape for paroxysmal nocturnal hemoglobinuria (PNH) has been revolutionized by complement-targeted therapies, with approved anti-C5 monoclonal antibodies and C3 inhibitors significantly reducing hemolysis and thrombosis. However, challenges such as breakthrough hemolysis, persistent extravascular hemolysis, and high therapeutic burden drive continued innovation.
| Therapy | Type | Targets | Mechanism of Action | Development Stage |
|---|---|---|---|---|
| Ravulizumab | Monoclonal antibody | C5 protein | Long-acting C5 inhibitor | Approved |
| Pegcetacoplan | Peptide conjugate | C3 protein | Binds C3 to prevent opsonization and hemolysis | Approved |
| Iptacopan | Small molecule | Factor B | Oral factor B inhibitor | Approved |
| Danicopan | Small molecule | Factor D | Oral factor D inhibitor | Phase III |
| Crovalimab | Monoclonal antibody | C5 protein | Self-administered C5 inhibitor | Phase III |
| BCX9930 | Small molecule | Factor D | Oral alternative pathway inhibitor | Phase II |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
At Protheragen, our unwavering commitment lies in delivering state-of-the-art diagnostic and therapeutic development services tailored specifically for paroxysmal nocturnal hemoglobinuria (PNH), a challenging bone marrow failure disease. Our expertise is centered around the development of innovative therapies spanning multiple molecular classes, meticulously studied in intricately crafted disease models during the preclinical phase.
Animal Model Development Services
Protheragen is focused on creating genetically engineered and xenograft models that replicate the features of paroxysmal nocturnal hemoglobinuria (PNH).
Specializing in preclinical research for drug development, Protheragen offers a comprehensive solution that includes pharmacodynamics (PD), pharmacokinetic (PK) and toxicology studies to thoroughly validate and optimize therapies for paroxysmal nocturnal hemoglobinuria (PNH). If you are interested in our services, please feel free to contact us for more details and quotation information of related services.
Reference
Myeloproliferative Disorders (MPDs)
Bone Marrow Failure Syndromes (BMFS)
