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Mitochondrial Gene Variance, Killing Cancer Cells, NICU Stress Effects, Visually Impaired Driver Safety

Published on March 22, 2019 in Cornerstone Blog · Last updated 3 months ago


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In this week’s news roundup, there’s a lot to be proud of as our researchers make impactful discoveries, such as new-found variability in a mitochondrial disease-causing gene and encouraging findings about an antibody-drug conjugate that targets a surface protein expressed in childhood neuroblastomas, effectively killing cancer cells. Wanjiku Njoroge, MD, and colleagues followed mothers of very preterm infants to determine stress in the NICU and its effects five years later, and Allison Curry, PhD, MPH, is changing perceptions about visually impaired drivers. Finally, just in case you missed it, we’re shouting from the rooftops that the Department of Pediatrics at Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania has, for the seventh consecutive year, been named as the number one pediatrics department in the United States.

Mitochondrial Disease-Causing Gene has Varied Effects

Mutations in a gene located in the DNA of mitochondria have been classified as a mitochondrial disease and linked to a particular set of symptoms. Mutations in this gene, which encodes an essential part of the mitochondrial motor known as ATP synthase that generates cellular energy, are more variable than previously thought, according to new findings from researchers at Children’s Hospital of Philadelphia, The study results, published online Feb, 14 in the journal Human Mutation, suggest the need for more precise clinical tests to better determine the course of treatment for patients with mitochondrial disorder.

Mitochondria contain 37 genes encoded in their own DNA (mtDNA) that are separate from the DNA found inside the nucleus of the cell. Variations in more than 350 different genes located across both nuclear and mitochondrial DNA are responsible for causing mitochondrial diseases, which can cause more than 16 different symptoms and affect multiple organs.

Mutations in the mtDNA-encoded ATP synthase membrane subunit 6 gene (MT-ATP6) are found in between 10 and 20 percent of cases of Leigh syndrome, a progressive brain disorder long recognized as a form of mitochondrial disease, and another recognizable condition known as neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

Led by Rebeca Ganetzky, MD, attending physician in the Mitochondrial Medicine Frontier Program at CHOP, and an assistant professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania, researchers reviewed more than 200 reported cases of mitochondrial disease with an MT-ATP6 mutation to better understand the clinical presentation of its many variants. Dr. Ganetzky and her colleagues, including Marni Falk, MD, attending physician and executive director of the Mitochondrial Medicine Frontier Program, also presented a new clinical case series of 14 additional patients with MT-ATP6 variants of uncertain significance or relation to their medical problems.

They concluded that, despite having one common mutation, this is a particularly heterogeneous disease. The study identified a total of 34 variants within the MT-ATP6 mutation, where no single biochemical feature was shared by all individuals with these variants.

“This study provides an important point of reference for patients in whom MT-ATP6 variants are discovered in diagnostic testing, as we now recognize just how variable this disease may be,” Dr. Ganetzky said. “We need to develop better ways to test for this disease, since the classical clinical syndromic presentations of NARP and Leigh syndrome are not sufficient to capture the problems present in all of these patients.”

Antibody-drug Conjugate Efficacious Against Cell Surface Protein 

Yael Mossé, MD, a pediatric oncologist and researcher, is among the physician-scientists in the Cancer Center at CHOP who have developed a preclinical, potent therapy attached to an antibody that targets a surface protein expressed in most childhood neuroblastomas, effectively killing cancer cells. The researchers published their findings March 13 in Science Translational Medicine.

“If there is an ultimate 'bad guy' of neuroblastoma cell surface proteins — present on most tumors, but not on healthy tissues, and also vulnerable to immunotherapeutic targeting — this just may be it,” Dr. Mossé said.

The current findings build upon the 2008 discovery of mutations in the anaplastic lymphoma kinase (ALK) gene as the major cause of the inherited form of neuroblastoma, and found in about 14 percent of neuroblastoma tumors from patients with the most aggressive form of the disease.

Mossé and her team demonstrated that the ALK protein appears on the surface of most neuroblastoma cells and is not detectable on normal cells, indicating that ALK is a useful target for immunotherapy. Researchers worked with pharmaceutical colleagues to weaponize an antibody-drug conjugate (ADC), one of a rapidly growing class of anticancer agents. That ADC, called CDX-0125-TEI, combines a specific monoclonal antibody engineered to recognize ALK with a potent chemotherapy drug, an alkylating agent called thienoindole.

In cell cultures and animal models of neuroblastoma, the ADC-ALK approach killed neuroblastoma cells, with no discernible toxicity to healthy cells.

“This study is proof of concept that the ALK protein is a good immunotherapy target and, as we optimize this approach for the clinic, has the potential to be useful for the majority of aggressive neuroblastomas and to minimize the harsh consequences of therapy,” Dr. Mossé said, adding the findings could be relevant for other innovative immunotherapeutic strategies for hard-to-cure childhood cancers.

This research was supported with funding from the U.S. Department of Defense with additional support from Kolltan Pharmaceuticals, Solving Kids” Cancer and Braden’s Hope Foundation.

Maternal Depression and Stress in the NICU and at 5 Years

In a longitudinal study, Wanjiku Njoroge, MD, and coauthors followed a diverse sample of 74 very preterm ( ≤30 weeks’ gestation) children and their mothers to examine how maternal depressive symptoms and stress in the neonatal intensive care unit (NICU) are related to parenting behaviors at age 5 years.

Mother-child dyads were observed and coded for maternal intrusiveness, negativity, sensitivity, and positivity. Covariates including maternal and child intelligence, maternal education, income-to-needs ratio, maternal depression at age 5 years, and child gender were also included in multivariate analyses.

The interaction between maternal NICU stress and NICU depression for intrusiveness and negativity indicates that greater NICU depression was associated with more intrusiveness under medium or high levels of NICU stress, and more negativity under high levels of NICU stress. Greater NICU depression was also associated with less sensitivity, over and above other covariates.

Previous studies suggest that maternal postpartum mental health issues may have an impact on parenting and child development in preterm infants, but have often not measured symptomatology in the NICU or followed families through early childhood.

The findings, published in the March issue of the Journal of the American Academy of Child & Adolescent Psychiatry, suggest that early maternal peripartum depression and stress in the NICU can have lasting impacts on multiple parenting behaviors, highlighting the need for screening and targeted interventions in the NICU.

Dr. Njoroge is the medical director of the Young Child Clinic and a psychiatrist in the department of Child and Adolescent Psychiatry and Behavioral Sciences at CHOP, PolicyLab faculty member, and assistant professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania.

Young Drivers With Visual Impairments Not More Likely to Crash

You might think that adolescents and young adults with visual impairments would be at greater risk when driving, but a new study from CHOP researchers found otherwise.

Allison Curry, PhD, MPH, a senior scientist and director of Epidemiology and Biostatistics at the Center for Injury Research and Prevention, worked with researchers at Rollins School of Public Health at Emory University to study a large set of electronic health records. Together, the team examined licensure rates and police-reported crashes for adolescents and young adults with two of the most common types of vision impairment: unilateral vision impairment and amblyopia, also known as “lazy eye.” These conditions were examined since they cause reduced vision in one eye and decreased depth perception.

The researchers found that, while adolescents and young adults with these conditions were less likely to get licensed than those with no visual impairment, those who do drive were not more likely to be involved in crashes. This new information may be helpful for young adults with these conditions who might be reluctant to pursue obtaining a driver’s license.

Read more about the study, which was published in the Journal of the American Association for Pediatric Ophthalmology and Strabismus, on the Research in Action Blog.


CHOP Ranked Nation’s Top Pediatrics Department for 2020

What an accomplishment! For the seventh year in a row, U.S.News & World Report has ranked the Department of Pediatrics at CHOP and the Perelman School of Medicine at the University of Pennsylvania as the number one pediatrics department in the United States.

For 16 consecutive years, our pediatric program has received either first or second place in the country according to the magazine’s annual listing of best medical schools and other graduate programs. These rankings are designed for prospective students looking to advance their education interests and career goals, according to U.S.News. For those seeking to train within a department that is energized by the challenges of advancing pediatric medicine, this consistently high placement demonstrates CHOP is the place to be.

Read more about this achievement on Cornerstone, including thoughts from Joseph St. Geme, MD, physician-in-chief and chairman of the Department of Pediatrics, and congratulatory wishes from Madeline Bell, president and CEO of CHOP.

Catch up on our headlines from our March 11 edition of In the News:

  • Hematology Scientist Recognized for Hemophilia B Clinical Research
  • Madeline Bell Recognized for Outstanding Leadership
  • New Preclinical Findings Explore Potential Treatment for Mitochondrial Disorders
  • New Study Finds Vitamin D Supplementation Less Effective in Obesity
  • Study Team Tests Machine-learning Models’ Accuracy in Predicting Sepsis in Infants

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