Initial Safety and Target-Site Evaluation of a Manganese-Porphyrin-Based Compound for Subarachnoid Hemorrhage Treatment - Project Summary Subarachnoid hemorrhage (SAH) triggers a cascade of damaging events that contribute to high mortality rates and long-term neurological deficits. While the early brain injury in SAH arises from an abrupt increase in intracranial pressure, causing immediate brain cell damage, secondary injuries, including delayed cerebral ischemia (DCI), present additional challenges to patient recovery. The pathophysiology of the early and secondary brain injuries after SAH is complex and dynamic, with the overproduction of free radicals playing a significant role in both injury phases. Despite the well-recognized roles of oxidative stress in SAH, the clinical translation of anti-free radical agents has been hindered. Expert opinions have pinpointed critical issues in the preclinical studies that formed the basis of clinical translations, including inadequate demonstration of BBB penetration, absence of drug concentration (PK) and biological activity (PD) assessments at the target site, and reliance on young male animals. This multi-PI R21 proposal seeks to evaluate the translational potential of MnP-05, a novel manganese porphyrin-based SOD (superoxide-dismutase) mimic, for SAH therapy. Our study design follows key recommendations from established guidelines and leverages our combined expertise in preclinical cerebrovascular disease research and drug development with a focus on pharmaceutical chemistry and PK/PD assessment. Our preliminary studies demonstrated MnP-05’s advantages, including (1) superior BBB penetration, (2) multifunctional anti-free radical activities through SOD mimicry, lipid peroxidation reduction, glutathione peroxidase (GPx) activity, and catalase activity, and (3) a favorable toxicity profile. In a pilot efficacy study in young male mice, MnP-05 showed promising improvements in short-term outcomes after SAH without causing hypotension or other toxicity. However, considering that the median age of SAH patients is 55–60 years, the relevance of findings from studies in young male mice may be limited. Additionally, the dose tolerated by young male mice may be toxic or cause hypotension in this older demographic. Hence, before advancing to a larger, long-term efficacy study, it is essential to determine whether MnP-05, at a well-tolerated dose, can improve SAH outcomes in animals representative of the target population, individuals over the age of 50. Aim 1 will identify a maximum tolerable dose (MTD) of MnP-05 in the primary target population, represented by male and female mice over 12 months old. Aim 2 will assess whether MnP-05 at the MTD effectively reaches the target site (PK), exerts the intended biological effects (PD), and improves short-term outcomes. The results from this study will answer the “go or no-go” question for further testing of MnP-05 as a therapy for SAH in a broader population. By assessing target site-specific PK/PD, we aim to confirm the intended biological effect of MnP-05 and provide essential data to guide dosing strategies for future studies.
