Significant neurodevelopmental delay is emerging as one the most important current challenges for patients
with congenital heart disease (CHD). Abnormal white matter (WM) development early in life accounts for the
type/degree of neurological deficits observed in children with CHD. In these children, WM is immature at birth
due to reduced oxygen supply in utero. Further WM injury after cardiac surgery commonly occurs in these
same individuals who have WM immaturity due to fetal hypoxia. Therefore, in order to reduce
neurodevelopmental deficits in the CHD population, it will be necessary to mitigate hypoxia-induced
WM immaturity in the fetus with CHD. However no treatment options are currently available.
Oligodendrocytes are the most prominent cell population in WM. Activation of nitric oxide synthase (NOS)
followed by production of the toxic peroxynitrite are crucial molecular events in oligodendrocyte toxicity due to
hypoxia-ischemia. Tetrahydrobiopterin (BH4) availability is significantly reduced upon activation of NOS and
leads to NOS uncoupling and production of the toxic peroxynitrite, causing oxidative stress. Importantly BH4
levels: i) increase during normal fetal development; ii) decrease in the hypoxic fetal brain; and iii) determine the
vulnerability of fetal brain to hypoxia-ischemia. Our data have demonstrated that in mice chronic hypoxia
causes a depletion of brain BH4 level. In addition BH4 supplementation during hypoxia rescues
oligodendrocyte dysmaturation and hypomyelination and improves hypoxia-induced motor coordination deficits.
These results have led to our principal hypothesis that decreased BH4 levels play a critical role in
triggering a series of oxidative stress reactions underlying immature WM development in the fetus with
CHD. Extensive safety records in the treatment of phenylketonuria demonstrate feasibility of BH4 treatment for
pregnant women. Marked improvements in WM injury have been found in children with phenylketonuria treated
early with BH4. Thus repurposing BH4 for use at the earliest feasible stage of brain development is a potential
therapeutic approach. Overall the aims of this proposal are designed to establish an optimal protective regimen
of maternal BH4 treatment for the fetus with CHD using our unique piglet model (Aim 1) and pharmacokinetic
approach (Aim 2). Leveraging sophisticated genetic tools and biochemical techniques in the mouse model, we
will elucidate poorly understood BH4 bioavailability and therapeutic actions of BH4 in oligodendrocyte
dysmaturation (Aim 3).
The proposed studies will establish a highly translational BH4 treatment aimed at reducing WM injury in CHD.
By defining mechanistic insight underlying BH4-induced WM recovery, our proposal has significant potential to
develop more targeted and effective treatment options for WM dysmaturation. The outcome of our studies will
likely benefit other populations in whom WM injury is a source of morbidity, such as premature infants.