Research Institute Archives

DOD $1.3M award will launch clinical trial to treat sarcoma

March 28, 2023

MPNST is a type of cancer called a sarcoma.

The Department of Defense (DOD) awarded Children’s National Hospital $1.3M to launch a unique clinical trial. The trial will evaluate the safety of a novel drug for patients with a rare but aggressive cancer known as malignant peripheral nerve sheath tumors (MPNST).

MPNST is a type of cancer called a sarcoma. While rare in the general population, about half of all MPNST are diagnosed in people with Neurofibromatosis Type 1 (NF1), a condition characterized by changes in skin coloring.

“MPNST is a life-threatening cancer for which there are no adequate medical options,” said AeRang Kim, M.D., Ph.D., director of clinical research of the Division of Oncology at Children’s National. “With the support of this grant, we will conduct a clinical trial to identify effective agents that could be of great benefit to all patients with NF1 who are at risk for sarcoma.”

MPNST are aggressive and frequently metastasize. The tumors that are not able to be removed with surgery rapidly progress and become lethal. In people with NF1, MPNST often develops within benign tumors, especially atypical benign tumors.

The hold-up in the field

Scientists have been looking at the cell signaling process within both pre-cancerous tumors and cancerous MPNST. Previous research has shown that the MEK and MDM2 signaling pathway influence the development and growth of these tumors. By blocking this interplay, the Zhu Laboratory at Children’s National has demonstrated that tumors can get smaller when treated with drugs that inhibit MEK and MDM2 in pre-clinical models.

What’s unique

The trial is uniquely designed to evaluate target inhibition of novel drugs by looking at signals that may help in determining tumor response. This work will provide people with NF1 and MPNST potentially helpful treatments and increase the knowledge for all people with NF1 and those at risk of MPNST. The drugs will be available to all patients who enroll to the study.

New research center focuses on origins of prenatal and neonatal disease

March 21, 2023

Children’s National Hospital researchers will develop new diagnostic tools and precision medicine for unborn children, babies and young children at the hospital’s newly established Center for Prenatal, Neonatal & Maternal Health Research.

The investment comes as research continues to show the importance of high-quality, evidence-based care at this crucial stage of pediatric development, especially for underserved families. The center is the sixth organization to join the Children’s National Research Institute.

What we hope to discover

“We know that many chronic diseases that crop up during adulthood have their footprint in the womb,” said center Director Catherine Limperopoulos, Ph.D. “While this concept has been around for years, our new center will provide a unique opportunity to study such research questions as the role of prenatal stressors on long-term outcomes. And we’ll be able to provide interventions earlier, improving mothers’ outcomes sooner. This benefits the mom, the fetus, the child and has implications for the next generation.”

Limperopoulos’s research will continue the hospital’s longstanding investment in improving the understanding, prevention and treatment of childhood diseases. The center will foster collaborations throughout the hospital by teaming with experts in neuroscience, oncology, genetics and other disciplines that are vital for safeguarding the health of mothers and their babies, even before they’re born.

The big picture

“We know that many chronic diseases that crop up during adulthood have their footprint in the womb,” said center Director Catherine Limperopoulos, Ph.D. “While this concept has been around for years, our new center will provide a unique opportunity to study such research questions as the role of prenatal stressors on long-term outcomes.

Limperopoulos will also continue to serve as the director of the Children’s National Developing Brain Institute, which focuses on the brain in utero, after birth and throughout preschool. Her research is paving the way toward understanding how maternal stress impacts fetal brain development and helping to advance perinatal mental health while addressing racial disparities in access to care. The center will also partner with clinical leaders throughout Children’s National and community partners to expand existing efforts, such as the DC Mother-Baby Wellness Initiative, an innovative program that Limperopoulos leads.

“The care of mothers and their young children will change dramatically in the next decade, and the breadth of our research has the power to lead the way in harnessing medical advancements to nurture healthier families,” Limperopoulos said. “Imagine a day when we can identify in utero a biomarker for a disorder such as sickle cell disease and prevent the disease from taking hold with a novel therapy. This is the vision for the groundbreaking research that will happen at the new center.”

Leading Wilms tumor research nationwide: Q&A with Jeffrey Dome, M.D., Ph.D.

February 22, 2023

Children’s National has become a resource for patients and families with Wilms tumor.

During the past year, Children’s National Hospital saw nearly 100 patients with Wilms tumor and other less common kidney cancers of childhood, far more than most centers in the country. This is largely due to the reputation the hospital has established for specializing in these diseases. While most patients with Wilms tumor have excellent outcomes, a significant minority of children with kidney cancer do not fare well. Children’s National has become a resource for patients and families with these challenging cancers.

Behind this reputation is Jeffrey Dome, M.D., Ph.D., senior vice president of the Center for Cancer and Blood Disorders and division chief of Oncology at Children’s National, and the team of researchers he leads. For over a decade, he chaired the Children’s Oncology Group Renal Tumor Committee, an opportunity that gave him and his work great exposure.

Dr. Dome shares more on how Children’s National is leading in this space and what the future holds for new, exciting Wilms tumor treatment options.

Q: How is Children’s National leading in this space?

A: The good news is that for the most common type of childhood kidney cancer, Wilms tumor with “favorable histology,” the survival rate is more than 90%, which is an incredible success story. But approximately 25% of children and teens with other types of Wilms tumor and other kidney cancers do not fare as well. We specialize in kidney cancers that are harder to treat, such as anaplastic Wilms tumor, relapsed favorable histology Wilms tumor, bilateral Wilms tumor, clear cell sarcoma of the kidney, malignant rhabdoid tumor and renal cell carcinoma. Because we see a relatively large number of patients, we can draw on our prior experience and observations to recommend the best treatment options.

Q: What’s unique about this research?

A: We have several early-phase clinical trials that are of interest for children with relapsed kidney tumors. Some of these trials are part of research consortia, such as the National Cancer Institute-funded Pediatric Early Phase Clinical Trials Network (PEP-CTN). Other studies have been developed in-house at Children’s National, including a couple of studies using T cells to target pediatric solid tumors. The T cells that have been engineered by the Children’s National Cellular Therapy Laboratory are of particular interest for Wilms tumor because they target a protein called WT1, which is expressed in most Wilms tumors. In fact, WT1 was named after Wilms tumor. We have now had more than 25 patients with relapsed Wilms tumor come from around the country to participate in these studies. Based on early successes, we are continuing this line of research and trying to improve the technology in the current generation of studies.

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.

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.”

Innovation in clubfoot management using 3D anatomical mapping

February 1, 2023

Idiopathic clubfoot is one the most common congenital deformities of the lower extremity. Its incidence is reported to be 1-2 cases per 1000 live births.

While clubfoot is relatively common and the treatment is highly successful, the weekly visits required for Ponseti casting can be a significant burden on families. Researchers at Children’s National Hospital are looking for a way to relieve that burden with a new study that could eliminate the weekly visits with a series of 3D-printed casts that families can switch out at home. The study, presented at the SPIE Medical Imaging Conference 2022, uses a novel photogrammetry method to gather 3D surface images of infant clubfoot anatomy and assess the foot position and correction.

Even better, this approach captures the images without additional radiation exposure.

“We’re not changing the gold standard of Ponseti casting, we’re adding to it,” says Sean Tabaie, M.D., orthopaedic surgeon at Children’s National and one of the study’s authors. “The more families we have in this study the greater the potential to move this field forward.”

Dr. Yang of Children's National Research Institute

Unlocking treatments for neuroblastoma

January 23, 2023

Dr. Jianhua Yang talks about his latest research into neuroblastoma treatments at Children’s National Hospital.

Curing neuroblastomas is going to take years of investigation and persistence, and the team at the Center for Cancer and Immunology Research at Children’s National Hospital is laying the foundation for breakthroughs. Recently, Jianhua Yang, Ph.D., and his colleagues completed a study providing proof-of-concept, preclinical evidence for exploring ulixertinib as a novel pharmaceutical approach for targeting neuroblastomas.

The big picture

This inhibitor blocks a type of communication inside a cell called the extracellular signal-regulated kinases (ERK), which are believed to drive the growth of neuroblastomas and various cancers. In a study of preclinical models published in Cancers, ulixertinib strongly inhibited the proliferation of high-risk neuroblastoma cells inside and outside of living organisms. Investigators also found that ulixertinib sensitized the cancer cells for treatment with the conventional chemotherapy drug, doxorubicin. Yang and his colleagues hope that finding inhibitors like ulixertinib could someday unlock a modality for treating neuroblastomas.

What we hope to discover

“We are trying to figure out if we can find a novel target, which no one has studied,” Yang said. “Some kinases, over-expressed in neuroblastoma and medulloblastoma, are interesting in terms of their expression pattern. We want to learn how they can be activated and promote tumor growth, and then we can develop therapies to safely target that cellular change.”

Neuroblastoma is the most common pediatric extracranial tumor, accounting for 15% of childhood malignancy-related deaths. Although some lower-risk versions of the disease can be cured, high-risk neuroblastomas have proven invulnerable to treatments for decades.

Moving the field forward

Working multiple research tracks, Yang’s lab is also investigating antibody-based immunotherapy that could be used to block the growth of neuroblastomas. Combined with chemotherapies, he and others at Children’s National believe these potential therapies could change the way pediatric cancers are treated and improve the quality of life for survivors.

“It’s like a religion,” Yang said. “You have to believe in yourself. The chance to fail is high, but you have to believe. If we can develop one or two drugs before my retirement, that’s a huge success.”

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.”

$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.”

Healthcare leaders join to advance pediatric innovation

December 21, 2022

Children’s National Hospital and the National Capital Consortium for Pediatric Device Innovation (NCC-PDI) have opened a request for proposal to solicit companies interested in obtaining pediatric labeling for medical devices that may address an unmet need in the pediatric population and that already have clearance or approval for adult use by the U.S. Food & Drug Administration (FDA). The objective of this program is to generate the real-world evidence (RWE) needed to facilitate the pediatric regulatory pathway for U.S. market clearance. The deadline to apply is 5 p.m. EST on Feb. 9. To learn more and apply, visit http://www.innovate4kids.org.

Instead of assessing medical devices based on data derived from clinical trials, this pioneering initiative is focused on leveraging real-world data (RWD) that can be translated into RWE to gain FDA clearance or approval for use with children.

Convening a coalition of healthcare leaders

The new partnership aims to address the significant gap that exists between devices labeled for adults and children. Additional coalition partners include:

CobiCure
MedStar Health Research Institute
Center for Technology Innovation in Pediatrics (CTIP)
UCSF-Stanford Pediatric Device Consortium
Pennsylvania Pediatric Device Consortium
Southwest National Pediatric Device Consortium

Funded by the FDA and facilitated through NCC-PDI and the Office of Innovation Ventures at Children’s National, this program will provide winning companies with technical expertise, including but not limited to regulatory, study design and data science services.

“We are delighted to partner with this coalition of trusted healthcare leaders that share our vision for advancing pediatric health. We know all too well that pediatric device development presents several unique challenges and that children have medical device needs that are considerably different from adults,” says Kolaleh Eskandanian, Ph.D., M.B.A, P.M.P, vice president and chief innovation officer at Children’s National and principal investigator of NCC-PDI. “There are already a number of medical devices on the market that have been FDA cleared or approved and proven viable, and this partnership will help provide important evidence generation and other wraparound services to guide device creators through the regulatory path for pediatric labeling.”

Using RWE to facilitate the regulatory pathway

While Randomized Clinical Trials (RCT) have traditionally been the gold standard when investigating a medical product’s efficacy and safety, many important populations, including children, are excluded from RCTs for ethical reasons. This means that pediatric researchers must make safety and efficacy decisions in the absence of data from such trials. RWE, including data from electronic health records (EHRs), healthcare claims data, disease registries and data gathered through other health applications, can close this gap in pediatric studies. She said that MedStar Health’s capabilities in applying RWE will be a formidable asset to the chosen applicants.

Proposals for companies seeking pediatric labeling for their medical device will be reviewed by an esteemed panel of judges specializing in data science, medical device development, evidence generation, post-market surveillance and the FDA’s regulatory pathway. Children’s National and members of the coalition will provide selected companies with technical expertise in support of their effort to achieve pediatric labeling. This will include:

Access to mentors
A design study protocol implementing RWE generation best practices
Facilitation of IRB submission and study implementation
Data science support
Regulatory, reimbursement and supply chain consultation

About NCC-PDI

NCC-PDI is one of five consortia in the FDA’s Pediatric Device Consortia Grant Program created to support the development and commercialization of medical devices for children. NCC-PDI is led by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National and the A. James Clark School of Engineering at the University of Maryland, with support from partners MedTech Innovator and design firm Archimedic.

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.

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.”

In the news: Novel research to stop pediatric brain tumors

November 22, 2022

“The team is really bringing in very new ideas from mathematical modeling, engineering, all the way to cell therapy, immunotherapy and immunology…This is what really excites and energizes us to be part of this great team, to address the Cancer Grand Challenge, to better target pediatric solid tumors.”

The Cancer Letter connected with Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital, for a conversation about her work as a leader of the Cancer Grand Challenges NexTGen team. The $25 million effort is funded by Cancer Research U.K. and the National Institute of Health’s National Cancer Institute and the Mark Foundation for Cancer Research. Its ambitious goal: find novel therapies to break the stalemate in the treatment of pediatric solid brain tumors in the next 10 years. Bollard shared her work plan and the “secret sauce” that gives the team its edge with The Cancer Letter. Find out more about the hope behind this effort in the full interview here.

NIH awards $1.8 million to trial pacemaker delivery system for children

November 16, 2022

The PeriPath access port makes it possible for pacing and defibrillating leads to be placed in the smallest children through holes the size of a straw.

A $1.8 million Small Business Innovation Research (SBIR) grant from the National Institutes of Health (NIH) is funding the first clinical trial of a novel device called PeriPath. The device makes it possible for pacing and defibrillating leads (or wires) to be placed in the smallest children through holes the size of a straw, eliminating thoracotomy or sternotomy procedures for children who are too small for transvenous implantation.

Even the tiniest pacemakers and defibrillators on the market today aren’t small enough for infants and young children with heart rhythm abnormalities. Innovating smaller devices, including adapting current technology like the Medtronic Micra for pediatric use, is a good start but won’t be enough to eliminate some of the challenges for these patients. When a newborn or young child needs any pacemaker or defibrillator, they face open chest surgery. Their arteries and veins are just too small for even the smallest size transvenous pacemaker catheter.

The research goal

Charles Berul, M.D., division chief of Cardiology and co-director of the Children’s National Heart Institute, partnered with engineers in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital to develop and test a first-of-its-kind minimally invasive pericardial access tool. The tool allows doctors to place pacing and defibrillation leads to the epicardial surface of the heart under direct visualization from an endoscope.

The team hypothesizes that this tool will allow for pacing and defibrillation therapy to be delivered through a single small port inserted through the skin that is about the size of a drinking straw.

Why it matters: Less pain, shorter and fewer surgeries

If successful, the device will eliminate the need for open chest surgery in patients who aren’t candidates for transvenous placement. The ability to place these leads percutaneously should:

Reduce pain and infection risk.
Decrease procedure times.
Minimize surgery complications that arise from open surgery.
Improve better visualization for pericardial punctures.
Allow other novel therapies such as epicardial ablation or, in the future, even drug/gene delivery into the pericardial space.

Any implanted pacemaker or defibrillator must be replaced every 5-10 years. A young child in critical need of such devices could face surgeries 10 or more times to replace the device and/or leads.

Pre-clinical testing shows early data that this percutaneous approach is as safe and effective as an open surgical technique, although it remains in early-stage evaluation.

What’s next

The NIH SBIR funding will allow the research team to assess long-term safety and efficacy and commercialize the PeriPath tool. Next steps are to:

Refine the design of PeriPath for production manufacturing, integrate testing protocols into a Quality Management System and conduct a pilot verification build. Success is defined as manufacturing production devices that pass 510(k) verification and validation testing.
Demonstrate substantial equivalence to predicate trocars through performance and handling validation testing using PeriPath to implant an epicardial lead in a pediatric simulator. If successful, the team will demonstrate equivalence and obtain investigational device exception (IDE).
In the latter part of the plan, to perform a first in human feasibility clinical study using PeriPath to implant a commercial pacemaker lead with institutional review board (IRB) approval in infants at Children’s National.

Bottom line

Dr. Berul says, “This research could have a transformative impact on current clinical practice by converting an open surgical approach to a minimally invasive percutaneous procedure.”

He also notes that while the study design focuses on the unique needs of infants and children with congenital heart disease – who are the primary focus of the device – the results of the trial may benefit thousands of adult patients who need pacemakers or defibrillators but who are not candidates for the transvenous placement.

Catherine Bollard at People V. Cancer summit

In the news: People v. pediatric cancer

November 15, 2022

“I just want to hammer home the fact that, if you have a child with a pediatric solid tumor who relapses, most likely the chemotherapy that will be treating that child will be the same chemotherapy that a child diagnosed 20 years ago would have received. This is how little progress has been made…. This is what we are trying to change.”

Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National Hospital, pulled the curtain back on her work fighting pediatric brain tumors at The Atlantic’s People V. Cancer summit. This annual event brings together leading voices from the front lines for in-depth conversations about how to stop this complex and lethal disease. Dr. Bollard discussed the unique importance of collaboration among pediatric oncologists and the optimism she has for using a patient’s immune system to go after solid tumors with CAR T therapies.

Building “digital twins” to test complicated surgeries

November 3, 2022

Syed Anwar, Ph.D., is developing self-supervised algorithms for medical imaging.

Syed Anwar, Ph.D., joins the growing AI initiative in the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI) at Children’s National Hospital with extensive research experience in machine learning and medical imaging from the University of Engineering and Technology in Taxila, Pakistan, the University of Sheffield, U.K., and the University of Central Florida through the Fulbright Scholars Program. At Children’s National, he’s grateful for the proximity between researchers and clinicians as he studies federated learning and works to build “digital twins” that allow medical teams to test complicated surgical and treatment plans on infants with disorders including Pierre Robin Sequence. This rare congenital birth defect is characterized by an underdeveloped jaw, backward displacement of the tongue and upper airway obstruction. Anwar works alongside Marius George Linguraru, D.Phil., M.A., M.Sc., principal investigator at SZI, and the Precision Medical Imaging Lab to increase AI capacity in all areas of pediatric care at the hospital.

Q: What is the focus of your research work?

A: The main theme is a digital twin. It’s an engineering innovation that people have been using for some time, especially in manufacturing and aviation. For example, you can create a digital simulation of an airplane with a flight simulator. Now, people are starting to use the power of data-driven digital twins for medical applications.

I’m working to create a digital twin for infants born with Pierre Robin Sequence, where they need to have surgical interventions for improving the structure of the bones in the jaws. It includes a lot of clinical approaches, including surgery and ways to address apnea and food intake.

There are multiple areas of clinical expertise involved. With a digital twin, we will have a digital representation of the patient, and the surgeon, the radiologist and other clinicians can experiment with a proposed intervention before actually touching the patient.

Syed Anwar, Ph.D., joins the growing AI initiative in the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI) at Children’s National Hospital.

Q: How else are you using your engineering background in your research?

A: Another part of my work is federated learning, which is a type of machine learning. In artificial intelligence, we want big data as the starting point to train our deep learning models. When studying children, this is not always possible because we have smaller data sets.

Federated learning is a tool that helps in these situations. Data is kept at a local site. We train a model to learn from all that data at the different sites. One benefit is that we don’t need to share the data, which is very useful for preserving patient privacy. But you can still apply deep learning models and develop AI solutions using the distributed data for improved clinical outcomes.

Q: What do you see as the main hurdles you have to overcome?

A: For all medical data, and particularly for kids, the amount of data we see in a children’s hospital is small, particularly for rare diseases.

The second hurdle is good, quality labels. For example, if you are doing tumor segmentation, you still need to have some ground rules from a radiologist showing which part of the image is the tumor.

These challenges come together in another focus of my research – self-supervised learning, meaning we can train a machine to learn from the data itself, without the labels or ground rules. From a machine learning point of view, I am in the process of developing self-supervised algorithms for medical imaging and in general for medical data. It’s an amazing time to be in this research area and to enable the translation of AI driven solutions for clinical workflows.

Q: What excites you about being at Children’s National and working at SZI?

A: I come from an engineering background, and my research area has been medical imaging for some time, mainly magnetic resonance imaging. Before coming here, I was working at a university in Pakistan, teaching machine learning and conducting research related to medical imaging and biomedical signal processing. But I was missing strong connections with people caring for patients at the hospital.

Five winners selected in prestigious pediatric device competition

October 26, 2022

The National Capital Consortium for Pediatric Device Innovation (NCC-PDI) announced five awardees chosen in its prestigious “Make Your Medical Device Pitch for Kids!” competition. Each received a share of $150,000 in grant funding from the U.S. Food and Drug Administration (FDA), with awards ranging from $20,000 to $50,000 to support the advancement of pediatric medical devices.

Consistent with its mission of addressing the most pressing pediatric device needs, this year’s competition, moderated by MedTech Innovator, welcomed medical device technologies that address the broad unmet needs of children. The pediatric pitch event was part of the 10^th Annual Symposium on Pediatric Device Innovation, co-located with the MedTech Conference, powered by AdvaMed.

This year’s pediatric device innovation awardees are:

CorInnova – Houston, TX – Minimally invasive biventricular non-blood contacting cardiac assist device to treat heart failure.
Innovation Lab – La Palma, CA – Mechanical elbow brace stabilizes tremors for pediatric ataxic cerebral palsy to improve the performance of Activities of Daily Living (ADLs).
Prapela – Biddeford, ME – Prapela’s incubator pad is the first innovation to improve the treatment of apnea of prematurity in over twenty years.
Tympanogen – Richmond, VA – Perf-Fix replaces surgical eardrum repair with a nonsurgical clinic procedure
Xpan – Concord, Ont. – Xpan’s universal trocar enables safest and most dynamic access and effortless upsizing in conventional/mini/robotic procedures.

“We are delighted to recognize these five innovations with critical NCC-PDI funding that will support their journey to commercialization. Improving pediatric healthcare is not possible without forward-thinking companies that seek to address the most dire unmet needs in children’s health,” says Kolaleh Eskandanian, Ph.D., M.B.A, P.M.P, vice president and chief innovation officer at Children’s National Hospital and principal investigator of NCC-PDI. “We know all too well how challenging it is to bring pediatric medical devices to market, which is why we have created this rich ecosystem to identify promising medical device technologies and incentivize investment. We congratulate this year’s winning innovators and applaud their efforts to help bridge these important care gaps that are impacting children.”

Empowering Innovators

NCC-PDI is one of five consortia in the FDA’s Pediatric Device Consortia Grant Program created to support the development and commercialization of medical devices for children, which lags significantly behind the progress of adult medical devices. NCC-PDI is led by the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National and the A. James Clark School of Engineering at the University of Maryland, with support from partners MedTech Innovator and design firm Archimedic.

A pediatric accelerator program, powered by MedTech Innovator, the largest medical device accelerator in the world, is a key part of the network of resources and experts that NCC-PDI provides in support of pediatric innovators. All five of this year’s competition finalists had an opportunity to participate in the year-long accelerator program.

To date, NCC-PDI has mentored 250 medical device projects to help advance their pediatric innovations throughout all stages of the total product life cycle (TPLC).

Eskandanian adds that supporting the progress of pediatric innovators is a key focus of the new Children’s National Research & Innovation Campus, a one-of-its-kind ecosystem that drives discoveries that save and improve the lives of children. On a nearly 12-acre portion of the former, historic Walter Reed Army Medical Center in Northwest Washington, D.C., Children’s National has combined its strengths with those of public and private partners, including industry, universities, federal agencies, start-up companies and academic medical centers. The campus provides a rich environment of public and private partners which, like the NCC-PDI network, will help bolster pediatric innovation and commercialization.

A total of $150K was awarded to five pediatric innovations during the medical device pitch competition at the 10th Annual Symposium on Pediatric Device Innovation, hosted by the National Capital Consortium for Pediatric Device Innovation (NCC-PDI). Award winners include (from left to right): Zaid Atto, founder and CEO at Xpan; John Konsin, CEO and co-founder of Prapela; Elaine Horn-Ranney, co-founder and CEO at Tympanogen; William Altman, CEO at CorInnova; and Sharief Taraman, pediatric neurologist at CHOC and University of California-Irvine partnering with Innovation Lab. (Photo credit: Children’s National Hospital)

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.”