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Nobuyuki Ishibashi

R01 grant funds white matter protection study for congenital heart disease

Nobuyuki Ishibashi

Nobuyuki Ishibashi, M.D., is the principal investigator on a $3.2 million NIH R01 to study white matter growth and repair in utero for fetal brains affected by congenital heart disease.

Many of the neurological deficits seen in children with congenital heart disease (CHD) are related to abnormal white matter development early in life caused by reduced oxygen supply to the brain while in utero. Children with immature white matter at birth also commonly sustain additional white matter injuries following cardiac surgery.

The NIH recently awarded a prestigious R01 grant totaling more than $3.2 million to a collaborative project led by the Center for Neuroscience Research, the Sheikh Zayed Institute for Pediatric Surgical Innovation and the Children’s National Heart Institute at Children’s National Hospital as well as MedStar Washington Hospital Center.

The research, titled “White matter protection in the fetus with congenital heart disease,” looks specifically at whether providing a supplemental amount of the naturally occurring tetrahydrobiopterin (BH4) for pregnant women could rescue white matter development of fetuses with congenital heart disease whose brains aren’t receiving enough oxygen – or suffering from hypoxic-ischemic events.

Previous preclinical studies have shown that this lack of oxygen depletes the brain’s natural BH4 level, and the researchers hypothesize that BH4 levels play a critical role in the growth and development of white matter in the fetal brain by triggering key cellular/molecular processes. Specifically, the study will focus on three aims:

  1. Establish in a preclinical model the optimal protective regiment for women pregnant with a fetus who has CHD to receive BH4.
  2. Determine the appropriate approach to deliver BH4 to this population
  3. Leverage genetic tools and biochemical techniques in the laboratory to better understand where and how BH4 levels play a role in the growth (or lack thereof) of oligodendrocytes—the primary cells of white matter.

This laboratory-based work is the first step to determining if the neurodevelopment of babies born with CHD can be preserved or recovered by addressing key brain development that occurs before the baby is even born. Findings related to congenital heart disease may also translate to other populations where white matter development is affected by hypoxia-ischemia, including premature infants.

The project is led by principal investigator Nobuyuki Ishibashi, M.D., with co-investigators Vittorio Gallo, Ph.D., Joseph Scafidi, D.O., and Mary Donofrio, M.D. as well as colleagues at MedStar Washington Hospital Center.

Joseph Scafidi

Developing brains are impacted, but can recover, from molecularly targeted cancer drugs

Joseph Scafidi

“The plasticity of the developing brain does make it susceptible to treatments that alter its pathways,” says Joseph Scafidi, D. O., M.S. “Thankfully, that same plasticity means we have an opportunity to mitigate the damage from necessary and lifesaving treatments by providing the right support after the treatment is over.”

One of the latest developments in oncology treatments is the advancement of molecularly targeted therapeutic agents. These drugs can be used to specifically target and impact the signaling pathways that encourage tumor growth, and are also becoming a common go to for ophthalmologists to treat retinopathy of prematurity in neonates.

But in the developing brain of a child or adolescent, these pathways are also crucial to the growth and development of the brain and central nervous system.

“These drugs have been tested in vitro, or in tumor cells, or even in adult studies for efficacy, but there was no data on what happens when these pathways are inhibited during periods when their activation is also playing a key role in the development of cognitive and behavioral skills, as is the case in a growing child,” says Joseph Scafidi, D. O., M.S., a neuroscientist and pediatric neurologist who specializes in neonatology at Children’s National Health System.

As it turns out, when the drugs successfully inhibit tumor growth by suppressing receptors, they can also significantly impact the function of immature brains, specifically changing cognitive and behavioral functions that are associated with white matter and hippocampal development.

The results appeared in Cancer Research, and are the first to demonstrate the vulnerability of the developing brain when this class of drugs is administered. The pre-clinical study looked at the unique impacts of drugs including gefitinib (Iressa), sunitib malate (Sutent) and rapamycin (Sirolimus) that target specific pathways responsible for the rapid growth and development that occurs throughout childhood.

The agents alter signaling pathways in the developing brain, including decreasing the number of oligodendrocytes, which alters white matter growth. Additionally, the agents also impact the function of specific cells within the hippocampus related to learning and memory. When younger preclinical subjects were treated, impacts of exposure were more significant. Tests on the youngest pre-clinical subjects showed significantly diminished capacity to complete cognitive and behavioral tasks and somewhat older, e.g. adolescent, subjects showed somewhat fewer deficits. Adult subjects saw little or no deficit.

“The impacts on cognitive and behavioral function for the developing brain, though significant, are still less detrimental than the widespread impacts of chemotherapy on that young brain,” Dr. Scafidi notes. “Pediatric oncologists, neuro-oncologists and ophthalmologists should be aware of the potential impacts of using these molecularly targeted drugs in children, but should still consider them as a treatment option when necessary.”

The effects are reversible

Researchers also found measurable improvements in these impaired cognitive and behavioral functions when rehabilitation strategies such as environmental stimulation, cognitive therapy and physical activity were applied after drug exposure.

“The plasticity of the developing brain does make it susceptible to treatments that alter its pathways,” says Dr. Scafidi. “Thankfully, that same plasticity means we have an opportunity to mitigate the damage from necessary and lifesaving treatments by providing the right support after the treatment is over.”

Many major pediatric oncology centers, including the Center for Cancer and Blood Disorders at Children’s National, already incorporate rehabilitation strategies such as cognitive therapy and increased physical activity to help pediatric patients return to normal life following treatment. The results from this study suggest that these activities after treatment for pediatric brain tumors may play a vital role in improving recovery of brain cognitive and behavioral function in the pediatric population.

This research was funded by grants to Dr. Scafidi from the National Brain Tumor Society, Childhood Brain Tumor Foundation and the National Institutes of Health.