Abstract Presentation Date: 6/8/2024Presentation Start Time: 6:00 PMBackgroundSickle cell disease (SCD), an inherited red cell disorder, generates abnormal (sickle) hemoglobin that polymerizes under hypoxic conditions. Sickle hemoglobin (HbS) polymerization produces sickled red blood cells (RBCs) and triggers vaso-occlusion and episodes of severe acute pain, also known as vaso-occlusive events (VOEs). These painful episodes are initiated by the adhesion of white blood cells (WBCs) to the endothelium via P-selectin, facilitating the binding of circulating sickle RBCs to WBCs. Subsequent polymerization of HbS within RBCs causes rigidity, leading to vessel occlusion and ischemia-induced pain. Concurrently, complement activation, a common pathogenic event in SCD, may exacerbate tissue damage and affect multiple cell types (RBCs, leukocytes, and endothelial cells), thereby also contributing to pain. Painful VOEs represent a hallmark complication of sickle cell disease (SCD) in adolescents and adults, often leading patients to seek medical care in hospital emergency departments. Despite advances in pain management, current SCD therapies lack effectiveness in modifying the course of VOE once initiated, leaving many patients with inadequate or incomplete treatment. Consequently, there is a pressing need for non-opioid-based therapeutic options that target the underlying mechanisms of VOE to provide more comprehensive pain relief and improve patient outcomes. We propose to prevent VOE pain by reducing the inciting event of WBC adhesion via P-selectin to the endothelium and reducing complement activation. IHP-102, a glycan-based therapeutic, targets multiple VOE-related mechanisms, including P-selectin and complement, and has been demonstrated to reduce pulmonary vessel occlusion in humanized SCD mice. This study aims to evaluate the analgesic efficacy of IHP-102 to reduce acute VOE-like pain behaviors in the Townes humanized SCD mouse model.MethodsAcute dose-response and longitudinal studies of IHP-102 will be conducted in Townes SS (SCD) and AA (control) mice. Both male and female mice (8 weeks old) will be utilized to explore potential sex-related effects. Acute VOE will be induced by hypoxia (5-15% O2) exposure and IHP-102 (0-60 mg/kg, subcutaneous, s.c.) will be administered at onset of reoxygenation. Behavioral (pain) testing for mechanical and thermal (hot & cold) hypersensitivity, as well as grip strength will occur 2-3 hours post-injection/exposure. In a longitudinal study, IHP-102 (30 mg/kg, effective dose for preventing vaso-occlusion) or the lowest effective dose will be administered daily for two weeks, with hypoxia exposure and behavioral testing every 3 days. After the final testing, mice will be euthanized, and blood/organs collected for biomarker analysis, including an assessment of organ damage. The impact of IHP-102 on cellular adhesion to a P-selectin-lined microfluidics device will be evaluated. Data analysis will involve ANOVAs and linear mixed models, reporting regression coefficients, standard errors, and 95% confidence intervals.ResultsWe anticipate that IHP-102 will significantly decrease acute and chronic pain behaviors in SS mice treated with IHP-102 compared to untreated controls, by reducing vaso-occlusion via P-selectin. We anticipate that targeting of complement activation will further contribute to pain reduction by mitigating tissue damage and inflammation associated with VOEs. By modulating complement-mediated pathways, we expect to observe improvements in vascular integrity and reduced leukocyte infiltration, leading to a decrease in overall ischemia-induced pain.ConclusionsIf successful in this pre-clinical animal model, IHP-102 will progress to human clinical trials. Conceptually, IHP is a game changing medication for SCD as current home treatment options are limited to non-specific anti-inflammatory and opioid medications. IHP-102 can be administered subcutaneously by individuals with SCD in their home, preventing further adhesion and vaso-occlusion in a disease-targeted manner, and reducing pain, opioid exposure, and need for hospitalization. Overall, we anticipate that the results of this study will provide valuable insights into the therapeutic potential of IHP-102 in alleviating acute VOE-like pain behaviors, offering a promising avenue for improving pain management and enhancing the quality of life for individuals with SCD.
