Keynote: Bioanalytical and Biomarker Strategies for Sickle Blood Cell Gene Editing Therapies

The pathophysiology of Sickle Cell Disease (SCD) is based on genetics, Hemoglobin-S (HbS) polymerization–dependent hemolysis and sickling, vaso-occlusion–dependent ischemia-reperfusion injury, endothelial dysfunction–dependent vasculopathy, and sterile inflammation. In low-oxygen environments, HbS can polymerize, causing red blood cells (RBCs) to distort into a characteristic sickle shape which slows or obstructs blood flow, resulting in vaso-occlusion and diminished oxygen delivery to surrounding tissues and organs. Membrane changes caused by HbS polymers lead to cellular dehydration, chronic hemolysis, and early cell death, causing anemia. Over time, hypoxia, hemolyis, anemia and vaso-occlusion may lead to progressive tissue and organ damage.

Our investigational therapy for SCD incorporates base edits that are designed to mimic single nucleotide polymorphisms seen in individuals with hereditary persistence of fetal hemoglobin (HPFH). BEACON is a Phase ½ study evaluating the safety and efficacy of a single dose of autologous CD34+ base edited hematopoietic stem cells to increase fetal hemoglobin (HbF) production in patients with severe sickle cell disease. Key bioanalytical strategies for our heme programs include methodologies to quantitate efficiency of gene editing at target alleles in peripheral blood (PB) and bone marrow (BM) cells and effects of treatment on total Hb, therapeutic Hb and sickle Hb.