Image-guided intra-arterial delivery of stem cells to repair brain damage after TBI

It is estimated that traumatic brain injury (TBI) accounts for over 2 million emergency department visits per year, and nearly 300,000 require hospitalization and treatment (CDC data). Those who serve in the military are at significant risk for TBI, with 414,000 cases reported among US service members between 2010-2019.

Consequences of TBI are often severe, including suffering for the victim, lost productivity, and burden on public health systems, with the costs of hospitalization and rehabilitation growing, as well as current inadequate treatments. Unfortunately, many patients develop lifelong neurological deficits. As the understanding of the

pathomechanism of TBI increases, attractive therapeutic targets are identified. Hence, there is hope of developing new therapeutic strategies that could be implemented early to halt the ongoing cascade of damage and at later stages, afford repair of brain damage. Pathomechanism of TBI is complex with multiple factors contributing to neurological deficits. TBI

triggers a strong and immediate inflammatory insult, with so-called “danger signals” or danger-associated molecular patterns (DAMPs) being potent activators of local immune responses, mediating secondary brain damage - especially adenosine triphosphate (ATP) and its receptor, P2X purinoceptor 7 (P2X7), whose

blocking has been studied with some success. However, following systemic administration, accumulation of these macromolecules in the brain is hugely ineffective. Over the last two decades, our research has focused on improving brain targeting with intra-arterial route being the most effective - as it facilitates minimally invasive

administration of high concentrations of drugs with immediate access within the entire lesion. Indeed, we confirmed experimentally that even during acute stage after TBI intraarterial targeting of brain lesion is feasible. This approach is ideal to address the needs of preventing TBI damages in the acute phase. As for the chronic

effects of TBI, recent studies focusing on war Veterans with TBI have revealed a preponderance of white matter abnormalities. Our group has worked extensively with glial restricted progenitor (GRP) cells; and we demonstrated quite spectacular therapeutic effects following transplantation in dysmyelinated mice. We have shown that

intra-arterially delivered GRPs can cross the blood-brain barrier; and thus, serve as a carrier for the local production of neuroinflammation-blocking nanobodies in brain parenchyma. Here we propose the “block-and- repair” therapy to address both the acute phase inflammation and the chronic phase white matter damage after

TBI. In this strategy, GRPs will be bioengineered with mRNA encoding a potent P2X7 nanobody to be secreted in situ to block inflammation, and GRPs will mature to repair white matter injury after TBI. To improve brain targeting for immediate effect, we will inject the cells using our established image-guided intra-arterial

technique. Our previous work showed functional improvement after TBI by depletion of microglia. In this proposal, we will explore if there is any additive effect with combined microglial depletion and P2X7nb-mRNA- GRPs. Overall, we propose an innovative cell-based strategy that addresses both acute and chronic

pathomechnisms following TBI. If our project demonstrates safety and efficacy of this approach, it could be rapidly implemented into clinical practice- potentially impacting the treatment of TBI.