A systematic scoring system to optimise the testing of neurotherapeutics in models of perinatal brain injury, with an applied case study of human umbilical-cord MSC

The preclinical stages of therapeutic agent development cost hundreds of millions of dollars, stymying innovation and slowing the development of products to improve human health. There is a striking unmet need for therapies that protect or repair the brain damage associated with preterm birth, i.e., delivery before 37 weeks of gestation. Of the more than 15 million babies born preterm every year, up to 60% will go on to develop a neurological disorder, with the earliest-born infants the most impacted. We have limited options with limited efficacy for preventing or treating these changes. Combining accurate knowledge of pathophysiology with high-throughput sequencing and computational biology approaches is a logical step towards an optimised screening pipeline. In this study, we conducted comprehensive testing of dose, timing, and route of administration, integrating multimodal data from preclinical models of brain injury common in preterm-born infants to validate the most effective therapeutic option for the cord-derived mesenchymal stem cell product (HuMSC). In this study, HuMSC serves as a working example, but the scoring system is therapy-agnostic. We developed a scoring protocol based on microglia transcriptome analyses and myelin protein expression to evaluate the efficacy of the HuMSC product in a rat model of inflammation-associated preterm infant brain injury. We identified the superiority of treatment delivered in the tertiary phase of injury over treatments in the acute or subacute stages, as well as the superiority of intranasal over intravenous delivery of HuMSCs. The optimal time, dose, and route of administration options for HuMSC were confirmed in a second model relevant to preterm infants, but with a different pathophysiology, namely germinal matrix haemorrhage. In conclusion, we have established a scoring protocol that expedites the collection of comprehensive dose, time and route of administration data critical for establishing large animal and clinical trials with the greatest chance of success.