Developmental delay and behavioral problems are emerging as the most important current challenges for children with congenital heart disease (CHD). Reduced oxygen delivery due to CHD in utero results in subnormal brain development. Newly-developed brain injury after cardiac surgery is also common in vulnerable neonates whose brains are already immature at the time of surgery. However, no treatment options are currently available for brain damage in children with CHD. Our studies have demonstrated that potential cell-based interventions for improvement of CHD-induced brain damage include: 1) promoting white matter regeneration through endogenous oligodendrocyte progenitors; 2) restoring the neurogenic potential of neural stem/progenitors; and 3) controlling microglia activation following cardiopulmonary bypass (CPB). Mesenchymal stromal cells (MSCs) are multipotent, non-hematopoietic cells that possess both immunomodulatory and regenerative properties, and can treat a wide range of diseases. Various rodent studies have shown that MSCs: 1) accelerate remyelination through the activation of endogenous oligodendrocyte progenitors; 2) promote neurogenesis from neural stem/progenitors; and 3) regulate microglia activation after hypoxic-ischemic brain insults. Multiple clinical trials have established the safety of allogeneic bone marrow (BM)-derived MSC-based therapy. We hypothesize that BM-MSC delivery to the early postnatal brain promotes endogenous regeneration of damaged neuronal and glia cells in children with CHD. Neonatal cardiac surgery provides a unique opportunity to control cerebral perfusion though CPB. We are proposing for the first time the use of CPB itself as a novel MSC delivery system in the CHD population. Our ongoing studies have demonstrated that: 1) CPB is an effective system for BM-MSC administration; 2) BM-MSCs modulate systemic inflammation following CPB; 3) BM-MSCs reduce CPB-induced microglia activation; 4) BM- MSCs inhibit caspase activation; and 5) there are no negative impacts after BM-MSC delivery though CPB. These results have led to our hypothesis that: BM-MSC delivery through CPB at the time of cardiac surgery is safe and improves neurodevelopmental outcome and postoperative course in children with CHD. To test the hypothesis we propose an open-label, dose-escalation, single-center phase I trial using a homogeneous population of infants with CHD who will be undergoing a two-ventricle repair within the first three months of life. In addition to the primary aim of assessing the safety and feasibility of BM-MSC delivery through CPB (Aim 1), our secondary aims (Aim 2 and 3) are designed to develop biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials with a particular focus on neurodevelopmental outcome and early postoperative course after BM-MSC treatment. The proposed studies will set the stage for a phase 2 trial of highly innovative BM-MSC treatment aimed at reducing neurodevelopmental disabilities and improving postoperative course in children with CHD.
New approaches to improve developmental delay and behavioral problems in children with congenital heart disease are urgently needed. This application seeks to develop a highly innovative cell-based treatment aimed at reducing neurodevelopmental disabilities and improving postoperative course in patients with congenital heart disease.
