Neurology and Neurosurgery Research

Center for Neuroscience and Behavioral Medicine announces new leaders

March 7, 2023

Elizabeth M. Wells, M.D., M. H. S., was named Senior Vice President of the Center for Neuroscience and Behavioral Medicine, and Lauren Kenworthy, Ph.D., was named division chief of Neuropsychology.

The Center for Neuroscience and Behavioral Medicine at Children’s National Hospital recently announced the appointment of two new leaders. Elizabeth M. Wells, M.D., M. H. S., was named Senior Vice President of the Center for Neuroscience and Behavioral Medicine, and Lauren Kenworthy, Ph.D., was named division chief of Neuropsychology.

Dr. Wells obtained her undergraduate degree in psychology and biology at Harvard University and her medical degree at the George Washington University School of Medicine and Health Sciences. She was an Intramural Research Training Award fellow at the National Institute of Mental Health and holds a master’s in Health Science from the NIH/Duke Clinical Research Training Program. She completed pediatrics and neurology training at Children’s National and joined the faculty in the Brain Tumor Institute in 2011.

Dr. Wells has led the Children’s National Inpatient Neurology program and developed the hospital’s multidisciplinary Neuro-immunology program into a destination program for unsolved neuroinflammatory diseases. She serves on numerous national and international associations and working groups and is a member of the scientific selection committee for the Child Neurology Society.

Dr. Wells has served in leadership roles for the Clinical and Translational Science Institute at Children’s National and the District of Columbia Intellectual and Developmental Disabilities Research Center. She is principal investigator for a 10-year translational research study within the Children’s National partnership with the National Institute of Allergy and Infectious Diseases and was the Children’s National Hospital Medical Staff President from 2020-2022.

Dr. Kenworthy received a B.A. from Yale University and Ph.D. from the University of Maryland. She completed her internship and residency training in clinical psychology/pediatric neuropsychology at Harvard Medical School, Children’s Hospital Boston, Johns Hopkins Medical School and Mount Washington Pediatric Hospital. She has been on the faculty at Children’s National and GW since 1995. She is a national leader in autism research, as well as a distinguished author and speaker.

Understanding the use of focused ultrasound in pediatrics

February 24, 2023

The fundamental principle of focused ultrasound (FUS) is almost analogous to using a magnifying glass to focus beams of sunlight on a single point. Experts at Children’s National Hospital are using FUS as an acoustic lens that uses multiple intersecting beams and targets — specifically deep within the brain — to treat brain tumors in pediatric patients.

Hasan Syed, M.D., co-director of the Focused Ultrasound Program at Children’s National, explains how two FUS methods are currently being used in two different trials — sonodynamic therapy and blood-brain barrier disruption — for the first time in pediatrics.

What is focused ultrasound?

FUS has diverse biological effects that can be categorized as thermal or mechanical: high-intensity focused ultrasound (HIFU) and low-intensity focused ultrasound (LIFU).

The treatments: 5-ALA with sonodynamic therapy and microbubbles for blood-brain barrier disruption

The difference between 5-aminolevulinic acid (5-ALA) medication and microbubbles has to do with the mechanism of treatment.

Dr. Syed explains that 5-ALA is activated by the focused ultrasound. Once activated, the goal is that the drug leads to tumor cell death.

Microbubbles, however, are used specifically to open the blood-brain barrier with focused ultrasound. When that happens, medications — or in our case the chemotherapy agents we’re using in our clinical trial — will hopefully have a better effect on treating the patient and taking care of the tumor.

Children’s National has now treated a series of patients with sonodynamic therapy — or LIFU and 5-ALA. There haven’t been any adverse events — the first time in the world that something like this has happened.

“I think it’s very exciting, and it brings us hope for new treatment options,” Dr. Syed said. Children’s National continues to recruit patients for this trial.

Tracking neurodevelopmental outcomes for kids with congenital heart disease

February 24, 2023

Extensive research has shown that children with congenital heart disease (CHD) who are born blue or who need cardiac surgery in their first year of life are at risk for developmental challenges and/or learning difficulties.

Mary Donofrio, M.D., co-director of the Cardiac Neurodevelopment Outcome (CANDO) program at Children’s National Hospital, says that we started the program — the only one of its kind in the Washington, D.C. region — to identify and manage delays in development and difficulties with learning, no matter when they arise.

“We start paying attention even before birth and then continue to evaluate neurodevelopment at key stages in a kid’s life to assure the best outcome. Our goal is for every kid born with CHD to be able to achieve their full potential, be active, make friends and succeed in school. Most important, we want each of our patients to grow up to be a happy and successful adult,” says Dr. Donofrio.

Learn more about CANDO at Children’s National Hospital and our role in developing best practices for neurodevelopmental and psychosocial services as part of the international multi-specialty Cardiac Neurodevelopmental Outcome Collaborative.

New deep learning system helps scientists edit RNA

February 16, 2023

The Children’s National team built DeepCas13 on a newer and less studied CRISPR platform, called CRISPR-Cas13d, which instead focuses on RNA.

Children’s National Hospital scientists have created a revolutionary machine-learning system that predicts the effects of changing ribonucleic acid (RNA) molecules using a gene-editing tool built on CRISPR technology.

Called DeepCas13, the system is among the world’s first deep-learning frameworks to recognize the challenges of editing RNA – and then applying data science and machine learning to solve the intricate problems that stem from modifying biological code. Details of the DeepCas13 system were published recently in Nature Communications.

Born from an international collaboration, DeepCas13 could provide the backbone for treatments for diseases based on errors in RNA, including debilitating neurodegenerative diseases such as Huntington’s disease and muscular dystrophy.

“I am an optimistic person, so I expect to have treatments within five to 10 years,” said Wei Li, Ph.D., principal investigator at the Center for Genetic Medicine Research at Children’s National. “Of course, there are going to be lots of obstacles. If we have a very good system, like DeepCas13, with very good performance that can generate treatments, the next problem is how we deliver the system to the right tissue in the patients.”

The big picture

Most research in this space has focused on a version of CRISPR – or Clustered Regularly Interspaced Short Palindromic Repeats – that edits DNA, called CRISPR-Cas9. The Children’s National team built DeepCas13 on a newer and less studied CRISPR platform, called CRISPR-Cas13d, which instead focuses on RNA. In doing so, researchers are opening the door to treating a host of disorders of RNA, given its biological role in coding, decoding, regulating and supporting gene expression.

DeepCas13 combines hundreds of thousands of data points with considerable computing power to help scientists target errant pieces of RNA, while minimizing any off-target changes that could damage the health of cells.

“We only want to target the RNA molecule that is causing diseases, and we don’t want the system to edit normal RNA,” said Xiaolong Cheng, Ph.D., a member of the Li lab and the first author of the study. “With DeepCas13, we can design highly efficient, and highly specific, rules.”

What’s ahead

The FDA has approved one method for delivering RNA treatments to cells, using a virus known as AAV or adeno-associated virus. So far, the gene therapy method has had limited applications. But Li and other researchers see the potential for life-changing treatments in the coming years, built on DeepCas13 and other advances.

The system was developed with partners from around the world, including the University of Illinois Urbana-Champaign and Northeastern University in Shenyang, China. It is open source and available for free to researchers looking for targets to treat RNA-related diseases.

Li says this international partnership is leading the way: “We tested our DeepCas13 model over other methods, and we confirmed that our method has the highest prediction accuracy.”

DeepCas13 was funded by grants from NIH and the Children’s National Research Institute.

Neuroprotective effect of Src kinase in neonates affected by HIE

February 8, 2023

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide.

In a systematic review published by Frontiers in Neuroscience, and co-authored by Panagiotis Kratimenos, M.D., neonatologist at Children’s National Hospital, Ioannis Koutroulis, M.D., pediatric emergency medicine physician at Children’s National and Javid Ghaemmaghami, M.S., researcher with the Center for Neuroscience Research at Children’s National, it was concluded that Src kinase is an effective neuroprotective target in the setting of acute hypoxic injury.

The paper reviews hypoxic-ischemic encephalopathy (HIE), a major cause of neonatal morbidity and mortality worldwide (one in four perinatal deaths is attributed to hypoxic-ischemic). While therapeutic hypothermia has improved neurodevelopmental outcomes for some survivors of HIE, this treatment is only available to a subset of affected neonates. Src kinase, an enzyme central to the apoptotic cascade, is a potential pharmacologic target to preserve typical brain development after HIE. This paper, a product of collaboration for a Master’s Thesis with the Aristotle University School of Medicine, Thessaloniki, Greece, where Dr. Kratimenos holds the appointment of Visiting Professor, presents evidence of the neuroprotective effects of targeting Src kinase in preclinical models of HIE.

The systematic review shows that while heterogeneity and risk for bias were limiting factors, the overall results indicate that Src-i neuroprotective properties could be a promising therapeutic strategy for neonates after hypoxic events.

Future TBI treatments may hinge on understanding a new cell type

February 7, 2023

Only recently have investigators begun to understand how a cell type – the NG2-glia – may respond to injuries, offering clues into the brain’s healing and regeneration.

Traumatic brain injury (TBI) afflicts 69 million people, including 630,000 children, worldwide each year. Yet only recently have investigators begun to understand how a cell type – the NG2-glia – may respond to injuries, offering clues into the brain’s healing and regeneration.

In a new paper published in GLIA, investigators from Children’s National Hospital reviewed 25 years of neuroscience research to lay out what’s known about the molecular response of these NG2-glia cells after TBI. Researchers said they see “a seductive possibility” that tapping into the regenerative potential of NG2-glia cells after neurotrauma could lead to therapies in the future. The impact could be profound, given that TBI is the leading cause of death among all people ages 1-44 and the global cost of this ‘silent epidemic’ is estimated to top $102 billion annually.

What they’re saying

“Our review lays out what’s known about these fascinating cells,” said Terry Dean, M.D., Ph.D., critical care specialist at Children’s National and investigator at the Center for Neuroscience Research (CNR). “NG2-glia are found throughout the brain, and we know that these cells undergo several dynamic changes in the hours, days and weeks after TBI. They are unique, and we want to understand their molecular characteristics to eventually enhance patients’ cellular recovery after TBI.”

Although only encompassing 4% to 8% of brain cells, these NG2-glia cells make up the largest population of regenerative cells in the adult central nervous system. In their article, Dean and Vittorio Gallo, Ph.D., Children’s National Research Institute interim director, lay out a number of unique features of these cells:

They proliferate, or multiply, and can form different cell types, especially after brain injuries.
They are structurally dynamic and can move and migrate throughout the cortex, including toward injury sites.
They appear to play a role in cell-to-cell signaling, which may prove vital after injuries.

The big picture

“As we study the brain after injuries, we hope our work will reveal the role these NG2-glia cells play in recovery, driving us to possible therapies,” Gallo said. “We believe the big answers will come through understanding the brain on a molecular level. This type of deep investigation is the foundation of our bench-to-bedside approach and positions researchers like Dr. Dean to find answers for our patients.”

Moving the field forward

Researchers have only begun to unlock how NG2-glia respond to injury, making this a fruitful area for research. Gallo, Dean and others at CNR hope to build on their knowledge about what happens to the brain immediately after an injury to learn more about what happens months after a debilitating impact. They are also considering new types of research models to expand their knowledge about cellular destruction, immune interaction and blood vessel compromise after different types of brain injuries.

“We look forward to the day when we have a truly targeted therapy for TBI patients,” Dean said. “Imagine the relief this could provide patients suffering from the persistent physical, cognitive and psychological disabilities that often accompany these brain injuries.”

Inducing strokes in newborns to treat hemimegalencephaly

February 3, 2023

“The number one thing people are perplexed by is how well these babies recover and how they can only live with half a brain,” said Tayyba Anwar, M.D., neonatal neurologist and co-director of the Hemimegalencephaly Program at Children’s National Hospital. “People think if a child has half a brain that’s damaged or dysplastic, how are they functioning? But babies are so resilient. It still amazes me.”

The big picture

Children’s National experts have pioneered a novel approach of inducing strokes to stop seizures and improve neurodevelopmental outcomes in newborns under three months old with hemimegalencephaly (HME).

The procedure, called an endovascular embolic hemispherectomy, can be safely used to provide definitive treatment of HME-related epilepsy in neonates and young infants, according to a study in the Journal of NeuroInterventional Surgery.

Prior to this approach, the standard treatment was an anatomic hemispherectomy — surgical removal of the affected half of the brain. But infants had to be at least three months old to undergo such a complex surgery. Delaying surgery meant the persistent seizures compromised the development of the healthy half of the brain.

What they’re saying

In this video, Dr. Anwar and Panagiotis Kratimenos, M.D., Ph.D., neonatologist and co-director of Research in Neonatology at Children’s National, discuss the critically important neonatal care provided to babies who undergo endovascular embolic hemispherectomy and how protocols have evolved with each case to make this less invasive approach a feasible early alternative to surgical hemispherectomy.

Drs. Anwar and Kratimenos are part of the multidisciplinary team of neonatal neurologists, neurointerventional radiologists, neonatologists and neurosurgeons performing endovascular hemispherectomies.

Gender Self-Report seeks to capture the gender spectrum for broad research applications

January 31, 2023

A new validated self-report tool called the Gender Self-Report provides researchers a way to characterize the gender of research participants beyond their binary designated sex at birth.

The multi-dimensional Gender Self-Report, developed using a community-driven approach and then scientifically validated, is outlined in a peer-reviewed article in the American Psychologist, a journal of the American Psychological Association.

The big picture

“This is the first broadly validated tool that allows us to measure inner gender experience across a large group of people in a rigorous way that doesn’t require a person to understand specialized gender-related terms,” says John Strang, Psy.D., who directs the Gender and Autism Program at Children’s National Hospital. He co-authored the journal article about the measure and co-led the initiative to develop it. “Typical gender assessments are fixed check boxes, which is problematic for capturing gender in people who are not familiar with many of the self-descriptors, which vary in their use and meaning.”

Strang notes that even open-field gender assessments can be problematic for people who experience gender diversity but are not aware of nuanced gender-related language.

Why it matters

This new gender characterization and inclusion method will allow researchers from a broad array of fields (e.g., social sciences, medicine, education) to model their participants’ inner gender experience more equitably in research. The resulting studies will be able to provide deeper understanding of how a person’s gender can play a role in study outcomes.

Senior author and statistical lead for the project, Ji Seung Yang, Ph.D., from University of Maryland Department of Human Development and Quantitative Methodology, foresees this tool as an important addition to the research toolkit for people studying neuroimaging, genetics and any other research that requires a more accurate and detailed picture of an individual’s gender experience.

What’s unique

The Gender Self-Report tool is the first of its kind to be developed and validated by researchers together with the gender diverse and neurodiverse communities directly. These efforts align with work in many fields of clinical research to ensure that study findings reflect the insights and experiences of the people who are being studied, rather than simply capturing the researcher’s external perspective of those participants.

The tool is appropriate for use by youth (as young as 10 years of age) and adults, gender diverse and cisgender individuals, and non-autistic and autistic people. The focus on inclusivity for autistic people is in keeping with the common intersection of autism and gender diversity (i.e., 11% of gender-diverse people are estimated to be autistic).

Gregory Wallace, Ph.D., co-author of the measure and associate professor in the Department of Speech, Language & Hearing Sciences at The George Washington University, calls the tool a “game changer for any research that needs to understand specifics about how gender experience can impact health-related or developmental differences.”

The Gender Self-Report: A Multidimensional Gender Characterization Tool for Gender-Diverse and Cisgender Youth and Adults, appears in the American Psychologist.

Extended rest might not always be best after a concussion

January 20, 2023

An early return to school may be associated with faster concussion recovery.

Contrary to popular belief, rest may not always be the best cure after a concussion, a new study published in JAMA Network Open finds. In fact, an early return to school may be associated with a lower symptom burden after suffering a concussion and, ultimately, faster recovery.

“We know that absence from school can be detrimental to youth in many ways and for many reasons,” says Christopher Vaughan, Psy.D., neuropsychologist at Children’s National Hospital and the study’s lead author. “The results of this study found that, in general, an earlier return to school after a concussion was associated with better outcomes. This helps us feel reassured that returning to some normal activities after a concussion – like going to school – is ultimately beneficial.”

In this cohort study, data from over 1,600 youth aged 5 to 18 were collected across nine pediatric emergency departments in Canada. Because of the large sample size, many factors associated with greater symptom burden and prolonged recovery were first accounted for through the complex statistical approach used to examine the data. The authors found that an early return to school was associated with a lower symptom burden 14 days post-injury in the 8 to 12 and 13 to 18-year-old age groups.

“Clinicians can now confidently inform families that missing at least some school after a concussion is common, often between 2 and 5 days, with older kids typically missing more school,” Dr. Vaughan says. “But the earlier a child can return to school with good symptom management strategies and with appropriate academic supports, the better that we think that their recovery will be.”

The findings suggest that there could be a mechanism of therapeutic benefit to the early return to school. This could be due to:

Socialization (or avoiding the deleterious effects of isolation).
Reduced stress from not missing too much school.
Maintaining or returning to a normal sleep/wake schedule.
Returning to light-to-moderate physical activity sooner (also consistent with previous literature).

Children’s National has been a leader in clinical services and research for youth with concussion, most notably through its Safe Concussion Outcome Recovery & Education (SCORE) Program. Given the multitude of other factors that can be expected to influence when a child returns to school after a concussion – including injury severity, specific symptoms, and pre-injury factors – a large sample size and complex statistical analytic approach was required. Future randomized clinical trials and other research can help determine the best timing for a student to return to school after suffering a concussion.

Bear Institute Pediatric Accelerator Challenge for Kids winners announced

January 19, 2023

In December 2022, the Bear Institute, along with Children’s National Hospital and Oracle Health, hosted the second annual Bear Institute PACK (Pediatric Accelerator Challenge for Kids), a start-up competition aimed to foster pediatric digital health innovation.

Bear Institute PACK is inclusive of the entire pediatric health care community and addresses the large disparity in digital health innovation funding dedicated to children versus the rest of the population. “We have to do more for children, a population that can’t advocate for itself,” says Matt Macvey, M.B.A., MS, executive vice president and chief information officer at Children’s National Hospital. “Bear Institute PACK is an all-hands effort to provide increased support to those start-ups trying to bring new solutions to market for kids.”

Start-ups share their innovations and receive valuable feedback from expert judges while competing for a chance to win an on-site pilot and software development support. The competition features three rounds of judging: an initial review of applications from the Bear Institute PACK team, judging from participating pediatric healthcare providers and administrators and review from an expert panel of judges during finalist start-ups’ live pitches. This year’s start-up participants competed across four innovation tracks in the following areas of development: Early-Stage Innovation, Concept Validation, Early Commercialization and Growth Trajectory.

This 2022 winners, in four innovation tracks, are:

Early-Stage Innovation (“Even the biggest ideas start small”) Winner: PigPug Health
Its solution uses neurofeedback, a non-invasive approach to treating brain-related conditions, and artificial intelligence to help children with ADHD and autism become more socialized.

Concept Validation (“Now it’s time to test it”) Winner: Global Continence, Inc.
Its Soluu™, Bedwetting Mitigation Device, helps rapidly and permanently mitigate bedwetting with a neuromodulation process.

Early Commercialization (“Countdown to launch”) Winner: PyrAmes Inc.
Its solution Boppli™ provides continuous, non-invasive blood pressure monitoring and streams data via Bluetooth to a mobile device.
Growth Trajectory (“The investment is growing”) Winner: maro
Its full stack child development kit equips a child’s caretakers (at home, school and clinic) with easy access to tools and data needed to help them navigate tough conversations including mental health, diversity, empathy, and puberty and helps identify mental health at-risk students in schools.

“I was very impressed with this year’s start-up participants and their caliber of talent and passion for what they do. The finalist judges were tasked with selecting one winner in each innovation track, but the work each participant is doing for kids makes them all winners,” says Rebecca Laborde, Ph.D., chief scientist, vice president of Health Innovation and Scientific Advisory, Oracle Health. “Thank you to the entire pediatric healthcare community that comes together to help make this event a success. We believe that by bringing together like-minded individuals with the same goals, we can make a real difference in pediatric healthcare.”

Harnessing children’s immune systems to fight their own brain tumors

January 13, 2023

Dalia Haydar, Pharm.D., Ph.D., principal investigator for the Program for Cell Enhancement and Technologies for Immunotherapies, recently joined Children’s National Hospital to help develop breakthrough treatments that hopefully will be a key in the fight against pediatric brain tumors. She brings her deep experience at St. Jude Children’s Research Hospital to the Center for Cancer and Immunology Research (CCIR) to help support the NexTGen team’s 10-year, $25-million Cancer Grand Challenges award.

Dalia – literally – has drive: She commutes 180 miles round trip from her home in Hershey, Pa., to her lab. She says she is grateful to be at one of the few research institutions in the world that is researching how to harness the power of CAR T-cell therapies to attack solid tumors in kids. While these therapies have been approved to treat leukemia and other blood cancers, solid tumors have proven far more stubborn. Haydar has tremendous hope that she and the team led by CCIR Director Catherine Bollard, M.D., M.B.Ch.B., will change that.

Q: Could you explain the importance of this research?

A: Unfortunately, once a patient is diagnosed with a brain tumor, especially a kid, there’s very little we can do. Using chemotherapy or radiation therapy has big disadvantages because of developmental delays and other side effects. We are hoping this kind of immunotherapy – where we take the patient’s own immune cells and engineer them in the lab to attack their cancer – will eradicate their very harsh and aggressive tumors, without causing significant adverse effects.

Q: How are researchers at Children’s National going to attack solid tumors with a treatment originally designed for blood cancers?

A: We have a lot of resources and expertise at Children’s National that we are trying to put together to develop a therapy that would cure brain tumors. Unfortunately, solid tumors are hard to treat and there are several challenges for any kind of immunotherapy. But right now, being at a place where all the necessary resources, support and expertise are available, we are hoping to address each of these challenges, and we are determined to do something in a meaningful timeframe to push that survival curve toward the advantage of those kids.

Q: How soon can this work be done?

A: Within two or three years, we are hopeful we’ll be able to identify the best working regimen of this CAR T-cell immunotherapy and investigate if it will work in a patient. I foresee, in the next 5 to 10 years, that we’re hopefully going to have such therapy for kids with brain tumors.

Q: What has surprised most you in your work?

A: There are so many challenges in developing immunotherapies for kids with brain tumors. First, if it works for adults, it doesn’t necessarily work for kids. Some of the tumors in kids are more aggressive. We need to understand the tumor itself, besides understanding the immunotherapy we’re developing.

The other challenge is CAR-T immunotherapy is not like a pill or taking radiotherapy that is standardized for several patients. It’s a very expensive therapy. It’s taking the patient’s own immune cell, like a bone marrow transplant. We put it in the lab, re-engineer the cells without transforming them into a cancer cell, enable those immune cells to attack the cancer, and then put them back into the patient. There are a lot of steps you need to take to make sure you don’t artificially harm those cells or introduce contamination.

One of the most intriguing challenges for me is how we make immunotherapy work for kids who have different kinds of brain tumors – a medulloblastoma versus a glioma versus an embryonal tumor. This is one of the challenges that keeps me on my toes, and I’m hoping to answer.

Q: What is the power of being in a multi-center environment like the Children’s National Research Institute?

A: We have to do enough science on the bench to support any proposal for the therapy to move to the clinic. The last thing we want to do is to investigate a drug or therapy in patients without really knowing how it works and the potential adverse effects. Being able to work with researchers at different stages of the bench-to-bedside spectrum, as well as being able to have access to patient samples and innovative preclinical models, helps push the science forward in a shorter time frame.

New model to treat Becker Muscular Dystrophy

January 12, 2023

Researchers at Children’s National Hospital have developed a pre-clinical model to test drugs and therapies for Becker Muscular Dystrophy (BMD), a debilitating neuromuscular disease that is growing in numbers and lacks treatment options.

Their work – recently published in the Journal of Cachexia, Sarcopenia and Muscle – provides scientists with a much-needed method to identify, develop and de-risk drugs for patients with BMD.

“The impact of having a model to test pharmaceutical options cannot be overstated,” said Alyson Fiorillo, Ph.D., principal investigator at the Center for Genetic Medicine Research at Children’s National. “We have patients coming up to us at conferences offering muscle biopsies – on the spot – because they are so excited and relieved that treatments can be investigated.”

Caused by mutations in a gene that produces a protein called dystrophin, Becker is part of a collection of disorders known as muscular dystrophies that cause a progressive loss of muscle strength and increasing disability, starting in childhood. The FDA has approved four drugs to help mitigate the impact of the most common and severe subtype, Duchenne Muscular Dystrophy (DMD). In some cases, these drugs convert the Duchenne form of the disease into Becker, which is less severe but still greatly affects quality of life.

As a result, the population of BMD patients is growing, but patients lack treatments for this incredibly impactful disorder. Currently, the FDA has not approved any drugs for BMD. Only two drugs are in clinical trials, compared to 30 trials underway for DMD.

To address this, Children’s National researchers used CRISPR gene editing to create the first preclinical model of X-linked BMD, called the bmx model. This novel advancement will help researchers better understand BMD and eventually create the first drugs for BMD patients.

“Patients with Becker need therapeutic treatments, and we are excited to start working with the model to someday provide options,” said Christopher Heier, Ph.D., principal investigator at the Center for Genetic Medicine Research and co-author of the study. “Most patients with Becker eventually develop cardiomyopathy, and roughly half die from it. This model is the first step on a path to change that and other heartbreaking outcomes from this genetic disorder.”

Abstract Happy 2022 New Year greeting card with light bulb

The best of 2022 from Innovation District

January 6, 2023

A clinical trial testing a new drug to increase growth in children with short stature. The first ever high-intensity focused ultrasound procedure on a pediatric patient with neurofibromatosis. A low dose gene therapy vector that restores the ability of injured muscle fibers to repair. These were among the most popular articles we published on Innovation District in 2022. Read on for our full top 10 list.

1. Vosoritide shows promise for children with certain genetic growth disorders

Preliminary results from a phase II clinical trial at Children’s National Hospital showed that a new drug, vosoritide, can increase growth in children with certain growth disorders. This was the first clinical trial in the world testing vosoritide in children with certain genetic causes of short stature.
(2 min. read)

2. Children’s National uses HIFU to perform first ever non-invasive brain tumor procedure

Children’s National Hospital successfully performed the first ever high-intensity focused ultrasound (HIFU) non-invasive procedure on a pediatric patient with neurofibromatosis. This was the youngest patient to undergo HIFU treatment in the world.
(3 min. read)

3. Gene therapy offers potential long-term treatment for limb-girdle muscular dystrophy 2B

Using a single injection of a low dose gene therapy vector, researchers at Children’s National restored the ability of injured muscle fibers to repair in a way that reduced muscle degeneration and enhanced the functioning of the diseased muscle.
(3 min. read)

4. Catherine Bollard, M.D., M.B.Ch.B., selected to lead global Cancer Grand Challenges team

A world-class team of researchers co-led by Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National, was selected to receive a $25m Cancer Grand Challenges award to tackle solid tumors in children.
(4 min. read)

5. New telehealth command center redefines hospital care

Children’s National opened a new telehealth command center that uses cutting-edge technology to keep continuous watch over children with critical heart disease. The center offers improved collaborative communication to better help predict and prevent major events, like cardiac arrest.
(2 min. read)

6. Monika Goyal, M.D., recognized as the first endowed chair of Women in Science and Health

Children’s National named Monika Goyal, M.D., M.S.C.E., associate chief of Emergency Medicine, as the first endowed chair of Women in Science and Health (WISH) for her outstanding contributions in biomedical research.
(2 min. read)

7. Brain tumor team performs first ever LIFU procedure on pediatric DIPG patient

A team at Children’s National performed the first treatment with sonodynamic therapy utilizing low intensity focused ultrasound (LIFU) and 5-aminolevulinic acid (5-ALA) medication on a pediatric patient. The treatment was done noninvasively through an intact skull.
(3 min. read)

8. COVID-19’s impact on pregnant women and their babies

In an editorial, Roberta L. DeBiasi, M.D., M.S., provided a comprehensive review of what is known about the harmful effects of SARS-CoV-2 infection in pregnant women themselves, the effects on their newborns, the negative impact on the placenta and what still is unknown amid the rapidly evolving field.
(2 min. read)

9. Staged surgical hybrid strategy changes outcome for baby born with HLHS

Doctors at Children’s National used a staged, hybrid cardiac surgical strategy to care for a patient who was born with hypoplastic left heart syndrome (HLHS) at 28-weeks-old. Hybrid heart procedures blend traditional surgery and a minimally invasive interventional, or catheter-based, procedure.
(4 min. read)

10. 2022: Pediatric colorectal and pelvic reconstructive surgery today

In a review article in Seminars in Pediatric Surgery, Marc Levitt, M.D., chief of the Division of Colorectal and Pelvic Reconstruction at Children’s National, discussed the history of pediatric colorectal and pelvic reconstructive surgery and described the key advances that have improved patients’ lives.
(11 min. read)

$1.6m grant to boost MRI access globally for maternal, child health

January 5, 2023

Hyperfine’s Swoop Portable MRI System

Researchers at Children’s National Hospital are investigating ways to bring more portable and accessible low-field magnetic resonance imaging (MRI) to parts of the world that lack access to this critical diagnostic tool, thanks to a grant from the Bill & Melinda Gates Foundation.

The nearly $1.6 million in funding will enable clinicians to better treat pediatric neurological conditions including ischemic brain injury, hydrocephalus, micro- and macrocephaly and more, using analysis tools that are designed to handle the loss in image quality and related challenges inherent to low-field MRI. The research brings together teams at Children’s National and Children’s Hospital Los Angeles — two organizations with extensive experience in designing processing software tools for pediatric brain MRI analysis and data enhancement.

The patient benefit

“For 30 years, MRI has primarily helped patients in high-income countries. Our team is thrilled by the prospect of expanding this powerful tool to patients coming from a wide range of nations, geographies and socioeconomic backgrounds,” said Marius George Linguraru, D.Phil., M.A., M.Sc., principal investigator at the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI). “Low-field MRI comes with great advantages including portability at the point of care of patients, lower clinical costs and the elimination of sedation for young children.”

Linguraru and his long-time collaborator, Natasha Lepore, Ph.D., principal investigator at The Saban Research Institute at Children’s Hospital Los Angeles, will analyze data from the brains of children from birth for the maternal and child health studies. The MRI data analyzed will form the basis for future studies of children’s brain anatomy in health and disease.

The big picture

Through the new grant, researchers will develop a suite of tools to help clinicians better analyze data and images from low-field MRI systems. These systems already have been integrated into interventional and observational studies to help characterize early neurodevelopmental patterns and identify drivers of abnormal development. They are also evaluating the efficacy of maternal and infant-focused interventions aimed at improving neurodevelopmental outcomes.

Why we’re excited

At Children’s National, SZI has installed a Hyperfine Swoop system, and Linguraru’s team is creating image enhancement tools tailored to the unique challenges of low-field MRI. Chief among them, conventional processing tools developed over the past several decades remain incompatible with the low-field data and require new software to take full advantage of the diagnostic power of imaging.

The work brings together a prestigious international consortium of scientists and clinicians from around the world to harness the power of computing and expand the reach of diagnostic imaging. Lepore said the team is eager to bring modern medical imaging to parts of the world that have missed its many benefits.

“Children’s brain development in underserved areas can be affected by so many factors, like malnutrition or anemia,” Lepore said. “The software we will design for the Hyperfine scanners will improve research into these factors, so the optimal interventions can be designed. We are excited to bring our expertise to this important and timely project.”

Effective treatment for children with hemimegalencephaly

December 1, 2022

Anatomic or functional hemispherectomy are established neurosurgical treatment options and are recommended for effective seizure control and improved neurodevelopmental outcome in patients with HME.

Endovascular hemispherectomy can be safely used to provide definitive treatment of hemimegalencephaly (HME) related epilepsy in neonates and young infants when intraprocedural events are managed effectively, a new study finds.

The authors of the study, which published in the Journal of NeuroInterventional Surgery, add that this less invasive novel approach should be considered a feasible early alternative to surgical hemispherectomy.

Why it matters

Anatomic or functional hemispherectomy are established neurosurgical treatment options and are recommended for effective seizure control and improved neurodevelopmental outcome in patients with HME. Hemispherectomy in the neonate, however, is associated with high surgical risks and most neurosurgeons defer surgical hemispherectomy until the patient is at least 8 weeks old. This delay comes at a significant neurocognitive cost as the uncontrolled seizures during this time of deferred surgery have a deleterious effect on future neurocognitive outcome.

Why we’re excited

“The procedure we have developed, endovascular hemispherectomy by transarterial embolization, acutely stops seizures and this cessation of seizures has been sustained in each of the treated patients,” says Monica Pearl, M.D., director of the Neurointerventional Radiology Program at Children’s National Hospital and the study’s lead author.

This treatment option – performed early in life – provides hope and a better quality of life for these patients post procedure.

What’s been the hold-up in the field?

Currently, the only effective treatment option is hemispherectomy. With the patient population of neonates and young infants, hemispherectomy has a very high mortality and complication rate resulting in most neurosurgeons deferring treatment until at least 8 weeks. This leaves neonates and young infants without effective treatment options and on multiple antiseizure medications in an effort to control the seizures

How does this work move the field forward?

“Embolization provides a highly effective treatment option that acutely stops seizures during a time period of critical neurodevelopment and one in which traditional open neurosurgical procedures are not viable options,” Dr. Pearl says. “Specifically, we can consider and perform embolization in children as young as one or two weeks of age rather than waiting until at least 8 weeks of age. The impact of earlier intervention – acutely stopping the seizures, reducing the dose and number of antiseizure medications and avoiding more invasive surgical procedures (hemispherectomy, shunt placement) – appears to be dramatic in our recent series. We are conducting long term studies to assess this effect on neurodevelopmental outcome.”

How is Children’s National leading in this space?

Dr. Pearl and the late Taeung Chang, M.D., neurologist at Children’s National, pioneered this concept and treatment pathway. The multidisciplinary team is led by Dr. Pearl, who has performed all the embolization procedures (transarterial embolization/endovascular hemispherectomy) and Tayyba Anwar, M.D., Co-Director, Hemimegalencephaly Program at Children’s National Hospital. Our epilepsy team, neonatology team and neurosurgery team work collaboratively managing the patients before and after each procedure.

Early SARS-CoV-2 exposure may impact infant development

November 30, 2022

The study found that some infants with in utero or early-life exposure to SARS-CoV-2 had borderline to low developmental screening scores.

Early SARS-CoV-2 exposure may impact neurodevelopment, especially among infants exposed in utero to symptomatic parents. This is according to a new study led by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital. Dr. Mulkey and team conclude that vaccination and other precautions to reduce early-in-life infection may protect against neurodevelopmental delays. Children with early SARS-CoV-2 exposure should have additional long-term screening for neurodevelopmental delays.

Children’s National Hospital leads the way

The developing brain is vulnerable to both direct and indirect effects of infection during pregnancy and in the early neonatal period. To chart the impact of this exposure, the team created a clinical follow-up protocol in the Congenital Infection Program at Children’s National to chart the development of 34 infants exposed to SARS-CoV-2 in utero or in the neonatal period.

What we hoped to discover

“We conducted this study because we know that infants, when exposed to maternal COVID-19 infection in utero can be exposed to inflammation, fever and an abnormal intrauterine environment. SARS-CoV-2 can also affect the placenta, and in turn, the developing brain,” Dr. Mulkey shared with Healio.

This study aimed to determine if infants with early SARS-CoV-2 exposure developed abnormal neurodevelopment in infancy and the factors that may impact neurodevelopment differences. The study found that some infants with in utero or early-life exposure to SARS-CoV-2 had borderline to low developmental screening scores, most common among babies born to mothers with symptomatic COVID-19. Researchers followed the infants in their first months of life, gauging how the exposure affected their neurologic development. Results were demonstrated using a screening test called the Ages & Stages Questionnaires (ASQ), and those whose scores were borderline or low were most often born to mothers with symptomatic COVID-19.

Why it matters

In conducting this study, the team found that babies born during the pandemic, specifically under these conditions, do, in fact, require additional follow-up in the early stages of life. We may also see more differences in developmental outcomes as children get older.

“Any measure we can take to help prevent infections for mothers in their pregnancy can improve long-term developmental outcomes for children,” says Dr. Mulkey.

Other members of the Children’s National team that contributed to this work include Roberta L. DeBiasi, M.D., M.S.; Meagan E. Williams, M.S.P.H.; Nadia Jadeed, R.N.C.; Anqing Zhang, Ph.D.; and Smitha Israel, B.S.N.

Dr. Mulkey also published a recent article in the American Journal of Obstetrics & Gynecology that found the COVID-19 vaccine may protect pregnant women from SARS-CoV-2 placentitis and stillbirth. This work builds upon Dr. Mulkey’s longitudinal studies on Zika virus infection in pregnancy and long-term impacts on the child, funded by the Thrasher Research Fund and the National Institutes of Health.

Exposure to Zika in utero may produce neurodevelopmental differences

November 30, 2022

“There are still many unanswered questions about the long-term impacts of Zika on children exposed in utero,” says Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital.

Children who are exposed to the Zika virus while in the womb, but who are not subsequently diagnosed with Zika-related birth defects and congenital Zika syndrome (CZS), may still display differences in some aspects of cognitive development, mood and mobility compared to unexposed children, reports a study published in Pediatric Research. These findings suggest that Zika-exposed children may need some additional support and monitoring as they get older.

“There are still many unanswered questions about the long-term impacts of Zika on children exposed in utero,” says Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital and the study’s first author. “These findings are another piece of the puzzle that provides insight into the long-term neurodevelopment of children with prenatal Zika virus exposure. Further evaluation is needed as these children get older.”

It has not been clear how children who were exposed to the Zika virus in the womb during the 2015–2017 epidemic, but who did not develop CZS and serious neurological complications, will develop as they get older.

Dr. Mulkey and colleagues examined the neurodevelopment of 55 children aged 3-5 years who were exposed to Zika in the womb in Sabanalarga, Colombia, and compared them to 70 control children aged 4-5 years who had not been exposed to Zika. Assessments occurred between December 2020 and February 2021. Health professionals tested the children’s motor skills (such as manual dexterity, aiming and catching, and balance) and their readiness for school (including knowledge of colors, letters, numbers and shapes). Parents completed three questionnaires providing information about their child’s cognitive function (such as memory and emotional control), behavioral and physical conditions (such as responsibility and mobility), and their parenting experience (including whether they felt distress).

Parents of Zika-exposed children reported significantly lower levels of mobility and responsibility compared to control children, although differences in cognitive function scores were not significant. Additionally, parents of 6 (11%) Zika-exposed children reported mood problems compared to 1 (1%) of control children, and Zika-exposed parents were significantly more likely to report parental distress.

Professional testing revealed no significant differences in the Zika-exposed children’s manual dexterity, such as their ability to catch an object or post a coin through a slot, compared to the control children. Both Zika-exposed and control children also scored lowly on readiness for school.

The authors highlight that parental responses may have been influenced by the Zika-exposed children’s parents’ perceptions or increased worry about the development of their child. Some differences in results may also have been caused by the age – and therefore developmental – differences between the groups of children.

The authors conclude that while these Zika-exposed children are making progress as they develop, they may need additional support as they prepare to start school.

Dr. Mulkey is committed to studying the long-term neurodevelopmental impacts that viruses like Zika and SARS-CoV-2 have on infants born to mothers who were infected during pregnancy through research with the Congenital Infection Program at Children’s National and in collaboration with colleagues in Colombia.

Autism Center of Excellence finds tools to avoid late diagnosis of women, others

November 29, 2022

Longitudinal data shows that girls and women are the most likely to be misdiagnosed or missed using traditional methods of assessment for autism.

The National Institute of Mental Health awarded $12.5 million to three institutions, including Children’s National Hospital, to become an Autism Center of Excellence. The goal of the research is to help autistic adolescents and adults receive timely and appropriate services and supports to improve overall outcomes. It is co-led by Lauren Kenworthy, Ph.D., at the Center for Autism Spectrum Disorders at Children’s National, Kevin Pelphrey, Ph.D., at the University of Virginia, and Allison Jack, Ph.D., from George Mason University,

The research will focus on developing screeners to identify people for autism assessment who traditionally have a high risk of a late or missed diagnosis.

Why it matters

Late or missed diagnosis puts people with autism spectrum disorder at greater risk for depression, anxiety and self-harm. It can also prevent access to supports through schools or other community organizations. Some people are misdiagnosed with other mental health conditions such as bipolar or borderline personality disorder leading to inappropriate treatments.

Longitudinal data shows that girls and women are the most likely to be misdiagnosed or missed using traditional methods of assessment for autism.

The hold-up in the field

There are two big reasons why truly autistic people fail to be identified. First, previous work to understand and diagnose autistic people was done based on data from mostly white, young, male participants. The tools do a very good job identifying autism that presents similarly to those study participants.

Kenworthy says the research community took a very long time (too long, perhaps) to recognize that many people with autism have a wide range of experiences both positive and negative that can inform diagnosis.

This relates to the second big hold-up in the field: that researchers have also been slow to recognize the importance of listening to the experiences of autistic people. Dr. Kenworthy says that for years, clinicians have known that diagnosing anxiety means asking the person how they feel inside. That same approach was rarely used with autistic people. “We need to listen to the people who are experiencing this or we are going to miss a lot,” she points out.

What’s next

The new Autism Center of Excellence has three main aims for the 5 years of funding.

Collect large amounts of behavioral and cognitive phenotyping data
Conduct qualitative interviews with autistic people using those data
Validate the development of the Self-Assessment of Autistic Traits — a tool that seeks to do a better job accelerating identification of people who need to be assessed for autism spectrum disorders but don’t necessarily meet the criteria of the current screeners.

Children’s National leads the way

This collaboration continues previous work the Center for Autism Spectrum Disorders has done with neuroimagers including Pelphrey and Jack to understand how autism and autism interventions affect the brain and builds on it by adding the experience of researchers from the autistic community.

The neuroimaging teams will use technology such as functional magnetic resonance imaging (fMRI), data analysis and genetic tools to find biomarkers and phenotypes that reflect what is learned from people with autism who experienced a missed or late diagnosis.

The end result will be a validated tool developed with people who experience autism, that gives people with autism, clinicians and researchers a unique new tool for identifying autistic strengths and challenges.

Kenworthy says it’s the two pieces coming together that will be the game-changer. “The technology, the biomarkers and phenotypes are really important, but aren’t meaningful until we understand how that maps onto the lived experience of autism.”

The psychosocial impact of food intolerances

November 10, 2022

Digestive illnesses involving food intolerances can bring unique challenges to pediatric patients and clinical management.

Digestive illnesses involving food intolerances bring unique challenges to clinical management. This is mainly due to their impacts on psychological and social functioning and reliance on elimination diets as primary treatment strategies.

In a review article published in the journal of Gastroenterology Clinics of North America, experts summarize psychosocial factors to consider in food intolerances as part of a larger special issue on topics pertaining to psychogastroenterology.

“Both pediatric and adult patients with celiac disease, non-celiac gluten sensitivity and eosinophilic esophagitis report increased anxiety-related symptoms,” says Shayna Coburn, Ph.D., psychologist at Children’s National Hospital and lead author of the article. “They also report hypervigilance-related eating, social ramifications including stigma and isolation and reduced quality of life directly related to food intolerances and dietary management.”

Experts at Northwestern University and Children’s Hospital Colorado also aided in this research.

The hold-up in the field

Integrated approaches using properly trained registered dietitians and clinical psychologists should be a mainstay for patients requiring long-term elimination diet treatment to mitigate some of these negative impacts, Coburn explains.

“Traditionally, gastrointestinal conditions are studied from a medical and biological perspective,” Coburn says. “Only recently has there been more emphasis on psychosocial factors in living with these conditions.”

The authors provide a narrative review to synthesize the clinical and research knowledge on the topic and inform practitioners from a range of disciplines.

How Children’s National Hospital leads the way

The Celiac Disease Program at Children’s National provides a specialized destination for families in need of evidence-based care and behavioral research opportunities for celiac disease and related conditions.

This work brings attention to the multitude of risks, stressors and challenges associated with food intolerances and aims to validate the struggles many face.

“We hope this article will serve as a reference for patient advocates to ensure appropriate emotional and behavioral support is provided when needed,” Coburn says.

This study brings together the similarities and differences in several conditions, and it is powerful how similar the challenges are across the diagnoses.

“It inspires us to consider more cross-cutting collaborative work to gain a bigger picture on the needs of patients with food intolerances and special diets,” Coburn says.

NIH awards $1m grant to study visual system

October 24, 2022

The team will focus its work on FXS, a genetic condition that causes changes in a gene called Fragile X Messenger Ribonucleoprotein 1 (FMR1).

Researchers at Children’s National Hospital received a $1 million grant from the National Institutes of Health (NIH) to study the neural mechanisms behind visual deficits in fragile X syndrome (FXS). The work will provide new insights into how the visual system develops.

With the award from the National Eye Institute, the Children’s National team – led by Jason Triplett, Ph.D., principal investigator at the Center for Neuroscience Research – will work to unravel the poorly understood relationship between sensory deficits and neurodevelopmental disorders (NDDs). The findings are expected to provide clues into possible non-invasive therapeutics that could someday be used to resolve visual deficits in children with FXS and other disorders.

“Deficits in sensory processing, including vision, are common in many NDDs, but how these deficits arise is poorly understood, hampering the development of therapies,” Triplett said. “Using a powerful combination of molecular, anatomic and electrophysiologic techniques, we are hoping to get a comprehensive understanding of visual circuit development – and its disruption in fragile X syndrome.”

The big picture

The team will focus its work on FXS, a genetic condition that causes changes in a gene called Fragile X Messenger Ribonucleoprotein 1 (FMR1). The gene normally makes a protein needed for brain development, including the highly complex visual system. However, people with FXS do not properly make the protein, leading to a spectrum of developmental and cognitive delays.

Triplett’s team theorizes that ameliorating sensory deficits could improve other features of the disorder. Research has shown that sensory processing is critical for communication and learning, which are central components of the behavioral therapies aimed at treating intellectual delays and social anxiety.

Yet little is known regarding the neural basis of sensory deficits in FXS. Understanding how neuronal circuits are disorganized and dysfunctional in the context of the disorder will be a critical first step to developing therapeutics. In addition, given the prevalence of sensory dysfunction across NDDs, the work could have broader applications.

Children’s National Hospital leads the way

This NIH-supported work builds on prior research in the Triplett Laboratory. The collaborative nature among investigators in the Center for Neuroscience Research combined with the technical resources supported by the DC-Intellectual and Developmental Disabilities Research Center create an environment that maximizes the experimental capabilities of the Triplett Lab.

“We are so excited to continue this work,” Triplett said. “It highlights the importance of supporting fundamental research at the bench. We started with basic biological questions about how circuits wire up, and now we are embarking on research that could set the stage for potentially life-changing therapies.”