Pang, Raymand; (2023) Translational Pipeline for Therapies to Treat Neonatal Encephalopathy Relevant to High and Low Resource Settings. Doctoral thesis (Ph.D), UCL (University College London).

Text Raymand Pang 20132153 PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2025. Download (24MB)

Abstract

Neonatal Encephalopathy (NE) is a leading cause of morbidity and mortality worldwide. Therapeutic hypothermia (HT) is the only treatment available, and although efficacious in high-income countries (HICs), infants still suffer from devastating long-term complications. Most concerningly, the safety of HT in low- and middle-income countries (LMICs), where the global burden of disease is greatest, remains unclear. This body of research aimed to assess several potential cytoprotective agents targeting the HICs (Part A) and LMICs (Part B) using two newborn piglet models. In Part A, a hypoxia-ischaemia (HI) model with 12h HT was used to assess adjunct agents suitable for clinical translation to HICs. The safety and efficacy of intravenous melatonin (non-ethanol formulation), Epo and their combination (triple therapy) to augment HT was assessed. Melatonin at 20mg/kg augmented HT, while Epo and triple therapy were not additive. To support clinical translation for melatonin, a preclinical meta-analysis was performed to pool the efficacy data in animal models of NE. This demonstrated robust brain protection and provided evidence that ethanol-containing formulations offer better protection. For LMICs (Part B), an inflammation-amplified hypoxia-ischaemia model was used to account for the contribution of infection/inflammation. Melatonin and azithromycin monotherapies were assessed as part of an adaptive preclinical neuroprotection trial. Both agents showed promising partial cytoprotection but required further optimisation. During the study, safety concerns regarding the cyclodextrin excipient in the melatonin formulation became apparent, limiting its translational potential. An ethanol-based melatonin formulation was assessed in a final study using a regimen that limited ethanol accumulation. This optimised regimen showed strong cytoprotection and provided vital safety and pharmacokinetic data to inform the next stage of clinical translation. The studies provided robust evidence to support the translation of melatonin to clinical trials for HICs and LMICs. Azithromycin showed promise, but further studies are needed with optimised dosing.

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