Human Neural Stem Cells (hNSCs) for neuroprotection in perinatal hypoxic-ischemic brain injury (HII)-Pre-IND-enabling Studies

The goal of our CIRM TRAN1 funding was to bring us closer to launching a Phase 1b/2a clinical trial using transplanted human neural stem cells (NSCs) for neuroprotection against perinatal hypoxic-ischemic brain injury (HII) which leads to hypoxic-ischemic encephalopathy (HIE), an essentially untreatable cause of cerebral palsy (CP) & neurological disability that occurs in 1-3/1000 newborns in the US and is 10-times more common in low-&-middle income countries (LMICs).   Toward that end, we succeeded in receiving written FDA feedback to our pre-IND meeting briefing document, and we held a follow-up meeting with the FDA clinical reviewers.   

HII is characterized by phases of neural cell death in the newborn’s brain. In the  immediate phase, cells die from a process called “necrosis” so rapidly that post-event neuroprotection is not feasible and these cells constitute a dead necrotic “core”. Cells surrounding the core (the “penumbra”) are damaged but still viable and are capable of being rescued from “delayed cell death”. In the later subacute phases (6-96 hrs. post-HII) the penumbral cells start succumbing to secondary causes of cell death. In this TRAN1 award we generated compelling preclinical data that transplanted NSCs can rescue the penumbral cells from dying.  

We have determined the optimal timing, dose, and route-of-administration parameters necessary for rescue of these penumbral cells.  Finally, we have developed an MRI tool (called “Hierarchical Region Splitting”) that can visualize and quantify (in animals or human babies) the extent of “penumbra” vs. “core” after an injury, and we can follow the evolution of the lesions in real time. That tool has helped us discern that NSCs are synergistic with standard-of-care (SOC) hypothermia (HT) treatment in normalizing the penumbra. Finally, we have carried out extensive molecular characterization of the cells at the level of both RNA and protein expression, to better understand the extent of homogeneity of the cell population and to develop a molecular signature, as well as an understanding of how these cells interact with the injured newborn brain (profiled molecularly for the first time).

Because administration of the hNSCs can be “piggy-backed” upon routine hospital care, monitoring, and follow-up of HIE babies receiving HT, we believe that hNSC use will become part of SOC and, hence, improve the lives of tens-of-thousands of children every year worldwide.