Thank you very much. Next speaker is Fatou Conteh, Non-Surgical Treatment to Prevent Post-Hemorrhagic Hydrocephalus of Prematurity. Good afternoon. My name is Fatou Conteh. I am a postdoc research fellow in the Robinson Lab at the Johns Hopkins Medical School. We have no conflicts to disclose. I'll present on a non-surgical treatment approach for post-hemorrhagic hydrocephalus of prematurity, or PHHP. PHHP results from early postnatal interventricular hemorrhage, or IVH, and currently is treated with surgery to divert CSF. As we all know, the outcomes for surgical intervention are poor and predisposes these children to ongoing morbidity. In many parts of the world, without access to surgery, PHHP also results in mortality. These images illustrate a common pattern with early postnatal IVH. Figure A is a coronal ultrasound that shows early postnatal IVH. B shows ventricular megaly. After a few weeks, C shows decompression of the ventricles after temporizing ventricular subgalea shunt, and D shows long-term ventricular decompression with a permanent shunt. Emerging work in the last five years by several labs has shown that motile cilia on ependymoma drives CSF flow. An example here shows the normal flow of CSF, which is color-coded in the mouse ventral third ventricle. Genetic mutants with impaired motile ependymoma cilia maturation develop symptomatic hydrocephalus with both ventricular megaly and progressive macrocephaly. These are coronal images from a human infant born at 28 weeks with severe IVH on day of life three and on day of life 13. Note the diffuse ependymal reaction throughout the ventricles. We predict that combining a prenatal model of chorioamnionitis with postnatal injection of lysed red blood cells in the lateral ventricles in rats will damage ependymomotile cilia throughout the ventricles, leading to abnormal CSF flow and progressive ventriculomegaly plus macrocephaly. We hypothesize that neonatal treatment with erythropoietin, EPO, plus melatonin can restore motile ependymoma cilia maturation and prevent hydrocephalus. EPO and melatonin individually are in clinical trials to test whether these endogenous hormones can mitigate CNS injury after extremely preterm birth. Our established rat model replicates PHHP in which prenatal injury via chorioamnionitis plus postnatal IVH depicted in the coronal head ultrasound leads to the diagnostic feature of ventriculomegaly and macrocephaly, which is evident in C, in which injured rats show progressive macrocephaly while control groups do not. Our new model of PHHP is unique in that, I'm sorry, our established rat model replicates PHHP in which prenatal injury via chorioamnionitis plus IVH so I'm sorry, our new model, sorry, of PHHP is unique in that rats with chorioamnionitis are injected very early at P1 and are age matched to appropriately correlate with human development. P1 in our model is equivalent, P1 is another word for postnatal day one, P1 is equivalent to very preterm human, about 30 weeks. On postnatal day two, P2, injured rats are randomized to extended treatments of EPO plus melatonin or VICO. At P16, a VICO treated injured rat exhibits a domed cranial vault while EPO plus melatonin treated rats, injured rats do not. VICO treated rats show progressive macrocephaly while the EPO plus melatonin treated rats do not. VICO treated rats show, I'm sorry, ventricular volume measured on MRI at P21 shows sham with and without IVH all had normal sized ventricles as shown in the blue bars on the left, while all VICO treated injured rats had ventricular megaly. After neonatal EPO plus melatonin treatment, 40% of injured rats had normal sized ventricles shown in the blue bar on the far right and the proportion with more severe ventricular megaly shifted to less severe as shown in the shorter red bar on the far right. Importantly, none of the EPO plus melatonin treated injured rats with residual ventricular megaly had progressive macrocephaly. In addition, on diffusion tensor imaging, reduction of fractional anisotropy in the central corpus callosum of VICO treated injured rats is prevented by EPO plus melatonin treatment. VICO treated injured rats exhibit elevated radial diffusivity in central corpus callosum and neonatal EPO plus melatonin treatment normalizes the microstructural integrity. Furthermore, the development of these rats were assessed through a battery of development tests. EPO plus melatonin treatment of injured rats prevents delayed performance on cleft aversion compared to VICO treated injured rats. The early work with our new model shows promise. The risk of developing post hemorrhagic hydrocephalus increases with very preterm birth, most often due to chorioimmunitis in infants with systemic illness plus early postnatal IVH, which subsequently damage epidermal motile cilia during a vulnerable developmental window. Importantly, this hypothesis suggests that motile cilia and the CSF flow may be repairable after injuries. This result I've shown suggests that early treatment with clinically available safe neuroreparative agents such as erythropoietin and melatonin can potentially restore motile epidermal cilia function and prevent symptomatic hydrocephalus. Our future work will investigate and clarify the mechanisms involved with EPO and melatonin to inform the development of novel, safe, and effective therapeutics for post hemorrhagic hydrocephalus of prematurity. Thank you very much. Thank you.

PHHP

EPO

melatonin

rat models

therapeutics