Prenatal Treatment for Brain Protection in Congenital Heart Disease

Doctor's Name: 
Nobuyuki Ishibashi, MD
Hospital/Institution: 
Children’s Research Institute, Washington, DC

Funded by Grant’s Gala

Worldwide, approximately 1.3 million infants are born with congenital heart disease (CHD) each year and this population is steadily rising. Over the six decades amazing advances have been made in reducing the mortality risk for patients across the entire spectrum of CHD. In the last 2 to 3 decades even the mortality of severe/complex CHD such as hypoplastic left heart syndrome (HLHS) has been reduced from close to 100% to less than 10%. However, it has been increasingly recognized that many children with severe/complex CHD suffer developmental delay, neurological impairment or behavioral problems. Such prolonged neurolodevelopmental deficits pose substantial socioeconomic and management challenges for patients, families, and society. Therefore, improving CHD-induced neurological deficits is not only a fundamental research endeavor: it is vital for the healthcare of this growing community of patients.

Fetal cerebral blood flow involves preferential streaming of the most highly oxygenated blood to the developing brain. However, carduac abnormalities can alter these beneficial patterns, resulting in less or oxygen-deficient cerebral blood flow. Since the heart is nearly fully developed by the 7th week of gestation, cardiac abnormalities can disrupt fetal cerebral oxygen delivery for more than 7 months during a period critical for brain development. Reduced oxygen delivery due to severe/complex CHD can result in sub-normal cerebral white matter (WM) development in utero. Furthermore newly developed WM injury after surgery is common in neonates who have preoperative WM immaturity secondary to fetal hypoxia. Clinical studies demonstrate that abnormal WM development early in life accounts for the type and degree of neurological deficits observed in patients with CHD. Therefore, in order to reduce neurological deficits in the CHD population, it will be necessary to mitigate hypoxia-induced WM injury in the fetus. However, no treatment options are currently available.

Based on evidences from our studies and others, we hypothesize that “Decreased tetrahydrobiopterin (BH4) levels play a critical role in triggering a series of molecular reactions underlying WM injury in the CHD fetus”. Extensive safety records in the treatment of phenylketonuria for pregnant women demonstrate feasibility of maternal BH4 therapy for the fetus with CHD. Thus, repurposing BH4 for use at the earliest feasible stage of brain development is a potential therapeutic approach. The Aims of this proposal are designed to establish an optimal protective regimen of maternal BH4 treatment that will limit WM injury in the fetus with CHD.

Aim 1. To define the optimal brain BH4 level that limits WM injury due to CHD and cardiac surgery

We will test the hypothesis that increased BH4 levels dose-dependently mitigate WM injury in the CHD fetus and reduce the risk of WM injury after CHD surgery.

We will investigate the developing mouse WM, which corresponds to the 3rd trimester in human WM development. Using our integrated and well-established mouse model of chronic perinatal hypoxia and cardiac surgery, we will define effects of the dose and duration of BH4 administration on hypoxia-induced WM injury (1-a) and WM injury after surgery (1-b). Finally an optimal brain BH4 level will be defined for protection against hypoxia-induced WM injury and injury after cardiac surgery (1-c).

 

Aim 2. To define optimal dose of maternal BH4 treatment in the fetus with CHD

BH4 was found to cross the placenta and distribute throughout fetal tissues including fetal brain. Thus we will test the hypothesis that maternal administration of BH4 dose-dependently increases fetal brain BH4 level. Dose-concentration-effects of maternal BH4 administration will be defined in a mouse gestational model (2-a). We will then determine endogenous human BH4 levels in the cord blood at different gestation ages in both normal and CHD fetuses (2-b). The results will be used to develop a mathematical pharmacokinetic model of BH4 administration during pregnancy, in order to establish an optimal regimen of maternal BH4 treatment for WM protection in the fetus with CHD (2-c).

The proposed studies will establish an innovative and highly translational BH4 treatment aimed at reducing the risk of WM injury in the fetus with CHD. Previous results from translational investigation in our laboratory have led to several clinical studies including four comprehensive prospective randomized trials. The resulting improved neurodevelopmental outcome will be of enormous benefit to individuals with CHD, their families, and our society.

Award Date 1: 
2015
Award Amount 1: 
$96,992
Award Date 2: 
2016
Award Amount 2: 
$97,742