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Five leading children’s hospitals secure funding to enhance future pandemic readiness

July 19, 2022

A group of children’s hospitals from across the country will coordinate on the response to future pandemics and other disasters through a new $29 million grant from the Health Resources and Services Administration (HRSA). The group, known as the Pediatric Pandemic Network (PPN), will focus on the unique needs and challenges to children during pandemics and disasters, ensuring that health equity is at the forefront of emergency planning.

The five hospitals are:

Children’s National Hospital in Washington, D.C. (lead institution)
Ann & Robert H. Lurie Children’s Hospital of Chicago
University of Alabama at Birmingham Department of Pediatrics at Children’s of Alabama
Children’s Mercy Kansas City
Seattle Children’s

“As the current pandemic has proven to the world, pandemics and public health crises magnify pre-existing environmental, health, social and economic inequities,” said Joelle Simpson, M.D., M.P.H., principal investigator of this grant and division chief of Emergency Medicine and medical director of Emergency Preparedness at Children’s National. “Communities of color not only feel the impact of pandemics and disasters far more severely than others, but also have more difficulty obtaining aid and assistance. If the needs of vulnerable populations are not addressed in emergency planning, the national disaster preparedness strategy could fail for all.”

The hospitals recognize that while the COVID-19 pandemic has been devastating for the entire world, the pediatric population in particular has been challenged by a lack of established coordination among pediatric care providers. In addition to addressing health equity, the funding facilitates the following:

Establishing pathways to gather and disseminate research-informed insights into how to care for children in a future pandemic to both medical providers and community organizations.
Developing a telehealth infrastructure to support the care of acutely ill children and expand mental health access.
Expanding pediatric-focused emergency preparedness and planning with a focus on behavioral health, social support, and educational services, all of which are typically provided by community organizations.

The hub for this grant will be located at the newly opened Children’s National Research & Innovation Campus – the site of the former Walter Reed Army Medical Center in Washington, D.C. Work will take place in the renovated Armed Forces Institute of Pathology, where past investigators made seminal discoveries in infectious diseases and pandemics. The former campus was named after Walter Reed because of his work around discovering the cause and prevention of outbreaks of yellow fever. This modern-day team of physician researchers intends to make equally important contributions to future pandemics and other disasters to help preserve the health of our nation’s children.

In September 2021, HRSA launched the Regional PPN by funding five pediatric hospitals to support the planning and preparation of children’s hospitals to respond to a global health threat. This new grant doubles the size and reach of the network in order to benefit all children in the nation.

Marshall Summar, M.D., receives Lifetime Achievement Award for rare disease work

June 27, 2022

For making strides to improve the lives of the rare disease community, the National Organization for Rare Disorders (NORD®) recognized Marshall Summar, M.D., with a Lifetime Achievement Award.

For making strides to improve the lives of the rare disease community, the National Organization for Rare Disorders (NORD®) recognized Marshall Summar, M.D., chief of the Division of Genetics and Metabolism and the director of the Rare Disease Institute at Children’s National Hospital, with a Lifetime Achievement Award.

This award honors individuals for outstanding career-long achievement on behalf of the rare disease community and commitment to improving the lives of those affected by rare diseases. It has been presented only a few times over NORD’s nearly 40-year history, most recently to former NIH Director Francis Collins, M.D., Ph.D., in 2015 and to clinician and researcher Robert Campbell, M.D., of Children’s Hospital of Philadelphia in 2018.

“I am honored to receive this award from NORD. It is so special to be recognized by the leading rare disease organization. This award comes from the work of so many people over the years, particularly our great team at Children’s National,” said Dr. Summar. “This acknowledgement of what we have done to date just gets me more excited about the future!”

Dr. Summar developed and launched the world’s first Rare Disease Institute at Children’s National in 2017, which is now located on the Children’s National Research & Innovation Campus, a first-of-its-kind pediatric research and innovation hub in Washington, D.C.

The institute, which includes the largest clinical group of pediatric geneticists in the nation, focuses on developing the clinical care field of the more than 8,000 rare diseases currently recognized and advancing the best possible treatments for children with these diseases.

Marshall and Karen Summar.

“Dr. Summar’s passion for serving patients is at the core of everything he does,” said Debra Regier, M.D., medical director of the Rare Disease Institute. “His mentorship for the next generation of medical and biochemical geneticists has become his legacy.”

The work Dr. Summar has done over the course of his career has resulted in new drugs in FDA trials for patients with congenital heart disease and premature birth. He also holds more than 60 patents and has published more than 160 peer-reviewed research studies.

“Beginning with his work as a clinician in the 1980s, Dr. Marshall Summar has spent a career forging partnerships, advocating at the highest level and developing new ways to treat rare disease patients,” said Peter L. Saltonstall, president and CEO of NORD.

“Dr. Summar served on the NORD Board of Directors for nine years, including six years as Chairman, and so we at NORD have been lucky enough to have years of firsthand experience with his leadership, community-building and innovation efforts in the rare disease field. This award is a recognition and appreciation for sustained excellence, including critical work with organizations such as the American College of Medical Genetics, the National Institutes of Health, NORD, and the Rare Disease Institute at Children’s National. For decades of commitment to families and organizations combating rare diseases, NORD is thrilled to present the Lifetime Achievement Award to Dr. Marshall Summar at the 2022 Rare Impact Awards,” Saltonstall added.

Learn more about the Rare Disease Institute at Children’s National.

Research into a new way to combat solid tumors earns part of a $25M award

June 27, 2022

Catherine Bollard, M.D., M.B.Ch.B., and Patrick Hanley, Ph.D.

Children’s National Hospital has developed multi-antigen specific T cells that have shown success in pre-clinical models in attacking pediatric solid tumors. Now the promising area of research earned a major boost from the Cancer Grand Challenges — founded in 2020 by the two largest funders of cancer research in the world – Cancer Research UK and the National Cancer Institute in the U.S.

This award supported the foundation of NexTGen, a team of scientists and clinicians with expertise in immunology, proteomics, mathematics and more, across eight institutions in the U.S., U.K. and France. Catherine Bollard, M.B.Ch.B, M.D., director of the Center for Cancer and Immunology Research at Children’s National, and Martin Pule, M.D., clinical associate professor at the University College of London are the co-leads of this effort.

The NexTGen team is one of four Cancer Grand Challenges’ new teams, representing a total investment of $100M to diverse, global teams to take on some of the toughest challenges in cancer research. NexTGen will create a new approach that performs clinical and basic research together to facilitate real-time knowledge exchange from the lab to the clinic and back again.

While the more widely known CAR-T cells have made tremendous progress for patients with B-cell leukemias, lymphomas and other blood cancers, the CAR T-cell field has not made the same impact for adult and pediatric solid tumors.

“A tumor cell is very clever because it tries to hide from the immune system by deleting or down regulating targets that the T cell is directed towards,” said Dr. Bollard.

Dr. Bollard further discusses the importance of having patient voices during the decision-making process in this quest, her hopes for their program and the concept of the combining tumor antigen-specific T cells with CAR-T cells that her team will develop.

Q: Can you explain the NexTGen vision?

A: The overall vision is that we will have developed the next generation of cell therapies to cure children with refractory solid tumors by the end of the five years. It is important to move the field forward, so we wanted to be innovative in our approach to this grand challenge for these children who have no other therapeutic options left.

Q: What are the most three important components of this project?

A: First, science and diplomacy played a significant role in bringing in the right set of investigators from diverse scientific backgrounds. What started as a conversation using the universal language of science, it quickly became an international project to address this complex issue. Second, we worked very hard with our patient advocates during the writing process, and they will be working side by side with the investigators at the bench and clinic. Third, we were the only group to have clinical trials in our proposal starting very early in the grant funding period, which is unprecedented.

Q: Can you describe NexTGen’s research model?

A: From our experience in leukemia, we know that progress is greatly accelerated if discovery occurs hand-in-hand with clinical development. Therefore, unlike classical programs where years of pre-clinical discovery and developmental work is required before the clinical translation, we will take a non-conventional non sequential approach.

Specifically, in the NexTGen Program, clinical development will start early with three cutting-edge clinical studies evaluating engineered T-cell technologies that we have recently developed understanding that there are some questions that can ONLY be answered in the clinic. To that end, clinical and translational data from these clinical trials will be able to feed into and enrich the discovery and pre-clinical science throughout the NexTGen Program in a circular fashion to promote this research program that goes from bedside to bench and back.

Q: How is Children’s National leading the way?

A: Children’s National is leading one of the three clinical trials that combine our non-gene engineered tumor antigen-specific T-cell platform with gene engineered T cells to generate a novel T-cell therapy against relapsed /refractory solid tumors. Combining tumor antigen specific T cells with the CAR T-cell platform represents a novel concept that may have more potency against these hardest to treat tumors in children.

Q: Why is it so important to include the patient voice during the discussion and decision making?

A: Because we are also physicians and scientists, we do not forget the patient and their families. Thus, we have a robust patient advocacy group embedded in this vision. The group will co-develop summaries explaining the challenges NextGen will address, how this will be achieved and how results will be used, with major input in clinical trial design and consent documents as well as key input into how patient tissue samples can be used to facilitate research discoveries. The patient advocacy team will also help find broad representation from multiple geographical locations of advocates with lived experience of different cancer types, including bereaved relatives and cancer survivors. These and many more strategies applied with patient advocacy groups will elevate the call for a broader and accelerated adoption of CAR-T clinical trials to broaden access to all patients.

Q: What excites you most about this?

A: What excites me the most is working with this incredible group of scientists, physicians and patient advocates all with rich and deep expertise who bring together an extensive and diverse knowledge base. The fact that we will be all working together toward a common goal of curing pediatric solid tumors in the next five to 10 years is extraordinarily energizing. This sizeable international collaboration comprises the right talent to get this done. It is also highly exciting to simultaneously have three clinical trials running in parallel with the discovery science and the pre-clinical work. I am extremely optimistic that we will realize NexTGen’s vision to bring next generation engineered T-cell therapies to the routine care of children with solid tumors within a decade.

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

June 16, 2022

Cancer Grand Challenges NexTGen team members (left to right): Amy Hont, M.D., AeRang Kim, M.D., Nitin Agrawal, Ph.D., Catherine Bollard, M.D., M.B.Ch.B., Conrad Russell Cruz, M.D., Ph.D., Patrick Hanley, Ph.D., and Anqing Zhang.

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 Hospital, has been selected to receive a $25m Cancer Grand Challenges award to tackle solid tumors in children. Cancer Grand Challenges is a global funding platform, co-founded by Cancer Research UK and the National Cancer Institute in the U.S., that supports a community of diverse, global teams to come together, think differently and take on some of cancer’s toughest challenges.

The Cancer Grand Challenges NexTGen team, co-led by University College London’s Martin Pule, M.D., will be working to develop next-generation cell therapies for children with solid cancers. Cancer is a leading cause of death by disease in children worldwide. Although survival has increased for some pediatric cancers, such as blood cancers, survival for some solid tumors has seen little improvement for more than 30 years. The team hopes to build a much deeper understanding of childhood cancers and develop and optimize novel therapies for children with solid tumors, ultimately hoping to improve survival and diminish the lifelong toxicities often experienced by survivors.

“With our Cancer Grand Challenge, we hope to bring next-generation CAR T-cell therapies to children with solid tumors,” said Dr. Bollard. “What excites me most is the energized, passionate group of people we’ve brought together to take this challenge on. Big problems remain to be addressed, but we believe they can be solved, and that we’re the team to solve them.”

“NexTGen represents crucial and overdue work. It has hope written all over,” said Sara Wakeling, patient advocate on the team and CEO and co-founder of Alice’s Arc, a children’s charity for rhabdomyosarcoma. “NexTGen hopes to transform the way these aggressive solid tumors are treated with less toxic side-effects, giving the children a real chance at growing up and realizing their potential. I’m so proud to be part of this exceptional team of scientists, clinicians and advocates who want to change the story for those diagnosed.”

The NexTGen team unites scientists and clinicians with expertise in immunology, proteomics, mathematics and more, across eight institutions throughout the U.S., U.K. and France. The Children’s National investigators that will also join are:

Nitin Agrawal, Ph.D., associate professor in the Center for Cancer and Immunology Research at Children’s National.
Conrad Russell Cruz, M.D., Ph.D.,principal investigator for the Program for Cell Enhancement and Technologies for Immunotherapies at Children’s National.
Patrick Hanley, Ph.D., chief and director of the cellular therapy program at Children’s National and leader of the Good Manufacturing Practices laboratory.
Amy Hont, M.D., oncologist in the Center for Cancer and Immunology Research at Children’s National.
AeRang Kim, M.D., oncologist in The Center for Cancer and Blood Disorders at Children’s National.
Holly Meany, M.D., oncologist in The Center for Cancer and Blood Disorders at Children’s National.
Anqing Zhang, biostatistician in the Biostatistics and Study Methodology Department at Children’s National.

The team, co-funded by Cancer Research UK, the National Cancer Institute and The Mark Foundation for Cancer Research, aims to bring much needed new treatments to children with solid cancers.

The NexTGen team is one of four new teams announced today as part of Cancer Grand Challenges, representing a total investment of $100m to diverse, global teams to take on some of the toughest challenges in cancer research.

“Cancer is a global issue that needs to be met with global collaboration. This investment in team science encourages diverse thinking to problems that have long hindered research progress,” said David Scott, Ph.D., director of Cancer Grand Challenges, Cancer Research UK. “Cancer Grand Challenges provides the multidisciplinary teams the time, space and funding to foster innovation and a transformative approach. NexTGen is one of four newly funded teams joining a scientific community addressing unmet clinical needs across cancer research.”

Find out more

Cancer Grand Challenges supports a global community of diverse, world-class research teams with awards of £20m/$25m to come together, think differently and take on cancer’s toughest challenges. These are the obstacles that continue to impede progress and no one scientist, institution or country will be able to solve them alone. Cancer Grand Challenges teams are empowered to rise above the traditional boundaries of geography and discipline.

Founded by the two largest funders of cancer research in the world – Cancer Research UK and the National Cancer Institute* in the U.S. – Cancer Grand Challenges aims to make the progress against cancer we urgently need. Cancer Grand Challenges currently supports more than 700 researchers and advocates across 10 countries, representing 11 teams are supported to take on 10 of the toughest challenges in cancer research.

The Cancer Grand Challenges NexTGen team, announced June 16, 2022, is taking on the initiative’s Solid Tumours in Children challenge. It is led by Dr. Bollard (Children’s National) and Dr. Pule (University College London), along with 23 co-investigators and 7 patient advocates, and is spread across eight institutions across the U.S., U.K. and France: Cardiff University; Children’s Hospital of Philadelphia; Children’s National Hospital; INSERM; the Institute of Cancer Research; Stanford Medicine; Stanford University; University College London. The Cancer Grand Challenges NexTGen team is funded by Cancer Research UK, the National Cancer Institute in the U.S. and The Mark Foundation for Cancer Research.

*The National Cancer Institute is part of the National Institutes of Health.

Children’s National named to U.S. News & World Report’s Best Children’s Hospitals Honor Roll

June 14, 2022

US News Badges Children’s National Hospital in Washington, D.C., was ranked No. 5 nationally in the U.S. News & World Report 2022-23 Best Children’s Hospitals annual rankings. This marks the sixth straight year Children’s National has made the list, which ranks the top 10 children’s hospitals nationwide. In addition, its neonatology program, which provides newborn intensive care, ranked No.1 among all children’s hospitals for the sixth year in a row.

For the twelfth straight year, Children’s National also ranked in all 10 specialty services, with seven specialties ranked in the top 10.

“In any year, it would take an incredible team to earn a number 5 in the nation ranking. This year, our team performed at the very highest levels, all while facing incredible challenges, including the ongoing pandemic, national workforce shortages and enormous stress,” said Kurt Newman, M.D., president and chief executive officer of Children’s National. “I could not be prouder of every member of our organization who maintained a commitment to our mission. Through their resilience, Children’s National continued to provide outstanding care families.”

“Choosing the right hospital for a sick child is a critical decision for many parents,” said Ben Harder, chief of health analysis and managing editor at U.S. News. “The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care.”

The annual rankings are the most comprehensive source of quality-related information on U.S. pediatric hospitals and recognizes the nation’s top 50 pediatric hospitals based on a scoring system developed by U.S. News.

The bulk of the score for each specialty service is based on quality and outcomes data. The process includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with the most complex conditions.

The seven Children’s National specialty services that U.S. News ranked in the top 10 nationally are:

Neonatology (No. 1), led by Division Chief Billie Lou Short, M.D.
Neurology and Neurosurgery (No. 3), led by Division Chiefs William D. Gaillard, M.D., and Robert F. Keating, M.D.
Nephrology (No. 5), led by Division Chief Marva Moxey-Mims, M.D.
Cancer (No. 6), led by Division Chief Jeffrey S. Dome, M.D., Ph.D.
Orthopedics (No. 7), led by Division Chief Matthew Oetgen, M.D., M.B.A.
Pulmonology and Lung Surgery (Tied for No. 8), led by Division Chief Anastassios Koumbourlis, M.D., M.P.H.
Diabetes and Endocrinology (No. 8), led by Division Chief Andrew Dauber, M.D., MMSc.

The other three specialties ranked among the top 50 were cardiology and heart surgery, gastroenterology and gastro-intestinal surgery, and urology.

LIFU successfully delivers targeted therapies past the blood-brain barrier

June 1, 2022

LIFU offers doctors the first opportunity to open the blood-brain barrier and treat the entire malignant brain tumor.

Children’s National Hospital will leverage low-intensity focused ultrasound (LIFU) to deliver therapy directly to a child’s high-grade glioma. The approach offers doctors the first opportunity to open the blood-brain barrier and treat the entire malignant brain tumor.

Children’s National will be the first hospital in the U.S. to treat high-grade pediatric brain tumors with LIFU to disrupt the blood-brain barrier. Crossing it has been a major hurdle for effective therapy. The barrier, a network of blood vessels and tissue, prevents harmful substances from reaching the brain but also stops molecular targeted therapy and immunotherapy from getting into the tumor site and staying there.

“LIFU gives us a way to potentially transiently open up the barrier, so we can deliver novel therapy directly to the tumor and improve the likelihood of survival,” said Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National. “It is the greatest breakthrough we’ve potentially had in the past 50 years or more for the management of these tumors. We made great strides in our understanding of molecular genetics and the molecular drivers of tumors, but we have not yet translated that knowledge into better therapies; this may be our most effective mechanism to overcome the barrier.”

In 2020, Children’s National was recognized as the first worldwide Center of Excellence by the Focused Ultrasound Foundation.

Focused ultrasound (FUS) is a non-invasive therapeutic technology with the potential to transform the treatment of many medical disorders by using ultrasonic thermal energy to specifically target tissue deep in the body. The technology can treat without incisions or the need of radiation.

How it works

Doctors at Children’s National will be using LIFU in two different types of procedures:

5-ALA: Doctors will give the patient 5-aminolevulinic acid (5-ALA) with the LIFU treatment. 5-ALA enters rapidly dividing cells and is activated by the ultrasound to a state where it kills the dividing cells of the tumor. The surrounding normal brain cells around the tumor are not dividing, so they do not take up the 5-ALA and are left unharmed after ultrasound therapy.
Microbubbles: While receiving different doses of LIFU over a one- to two-hour period, the patient is given “microbubbles,” which are widely used in medical imaging and as carriers for targeted drug delivery. These microbubbles bounce around against the walls like seltzer, opening the blood vessels and transiently opening that space.

Both studies are the first in the world for pediatric gliomas of the brain stem, allowing experts to treat patients 4-6 weeks after radiotherapy. The patient then receives medication orally or intravenously as it passes through the bloodstream. It does not go at high levels anywhere within the brain except where the blood-brain-barrier was opened, allowing oral medication or immune therapies to rush into the tumor.

The launch of this program comes a few months after the hospital successfully performed the first-ever high-intensity focused ultrasound surgery on a pediatric patient with neurofibromatosis.

Watch this video to learn more.

Pandemic-related stressors in pregnant women affect fetal brain development

May 26, 2022

Dr. Catherine Limperopoulos walking with a mom.

Prolonged levels of stress and depression during the COVID-19 pandemic contributed to altering key features of fetal brain development — even if the mother was not infected by the virus. This is what a study published in Communications Medicine suggests after following more than 200 pregnant women. The study, led by Children’s National Hospital experts, emphasized the need for more scientific inquiry to shed light on the long-term neurodevelopmental consequences of their findings and COVID-19 exposures on fetal brain development.

“Understanding how contemporary stressors may influence fetal brain development during pregnancy has major implications for basic science and informing public policy initiatives,” said Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National and senior author of the study. “With this work, we are able to show there’s a problem, it’s happening prenatally, and we can use this model to start exploring how we can reduce stress in moms and support unborn babies.”

To better understand the effects of environmental exposures on the fetus during pregnancy, further confirmation of the team’s latest findings is needed by ruling out other possibilities, such as maternal nutrition, financial security and genetic factors.

The psychosocial impact of COVID-19 on fetal brain development remains vastly understudied. The neurologic underpinnings of fetal development that turn into psycho-behavioral disorders later in life, including bipolar disorder, mood disorder or anxiety disorder, remain complex and difficult to explain.

Among the 202 participants from the Washington D.C. metropolitan area, 137 were part of the pre-pandemic cohort and 65 were part of the pandemic cohort.

Through advanced MRI imaging techniques and reconstruction of high-resolution 3D brain models, the researchers found a reduction of fetal white matter, hippocampal and cerebellar volumes and delayed brain gyrification in COVID-19 pandemic-era pregnancies. Validated maternal stress, anxiety and depression scales were also used to compare the scores between the two cohorts.

This study builds upon previous work from the Developing Brain Institute led by Limperopoulos, which discovered that anxiety in pregnant women appears to affect the brain development of their babies. Her team also found that maternal mental health, even in high socioeconomic status, alters the structure and biochemistry of the developing fetal brain, emphasizing the importance of mental health support for pregnant women.

“We’re looking at modifiable conditions,” said Limperopoulos. “What’s clear is the next frontier is intervening early to see how we can prevent or reduce stress in the mom’s current setting.”

Gene-targeting may help prevent or recover neonatal brain injuries

May 19, 2022

The findings of a new pre-clinical study published in The Journal of Neuroscience are helping pave the way toward better understanding, prevention and recovery of neonatal brain injuries.

The findings of a new pre-clinical study published in The Journal of Neuroscience are helping pave the way toward better understanding, prevention and recovery of neonatal brain injuries. During pregnancy, the fetus normally grows in low oxygen conditions. When babies are born preterm, there is an abrupt change into a high oxygen environment which may be higher than the baby can tolerate. These preterm babies often need support to breathe because their lungs are immature. If the oxygen they receive is too high, oxygen-free radicals can form and cause cell death.

Premature infants have underdeveloped antioxidant defenses that prevent or delay some types of cell damage under normal conditions. In a high oxygen environment, these underdeveloped defenses cannot fully protect against oxidative stress, damaging different brain regions without available treatments or preventative measures.

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the District of Columbia Intellectual and Developmental Disabilities Research Center. “I did not think we would be able to do it at a refined level, identifying cell populations sensitive to oxidative stress and its underlying signaling pathway and molecular mechanism.”

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, Ph.D.

Children’s National Hospital experts found that oxidative stress over-activates a glucose metabolism enzyme, GSK3β, altering hippocampal interneuron development and impairing learning and memory, according to the pre-clinical study. The researchers also inhibited GSK3β in hippocampal interneurons, reversing these cellular and cognitive deficits.

The role of oxidative stress in the developing hippocampus, as well as GSK3β involvement in oxidative stress-induced neurodevelopmental disorders and cognitive deficits, have both been unexplored until now. Goldstein et al. suggest the study paves the way for the field as a viable approach to maximize functional recovery after neonatal brain injury.

To better understand the mechanisms underlying neonatal brain injury, the researchers mimicked the brain injury by inducing high oxygen levels in a pre-clinical model for a short time. This quest led to unlocking the underpinnings of the cognitive deficits, including the pathophysiology and molecular mechanisms of oxidative damage in the developing hippocampus.

Once they identified what caused cellular damage, the researchers used a gene-targeted approach to reduce GSK3β levels in POMC-expressing cells or Gad2-expressing interneurons. By regulating the levels of GSK3β in interneurons ⁠— but not in POMC-expressing cells — inhibitory neurotransmission was significantly improved and memory deficits due to high oxygen levels were reversed.

Yves d’Udekem, M.D., Ph.D., named as The Baier Family Distinguished Professor of Cardiac Surgery

May 18, 2022

Yves d'Udekem Children’s National Hospital named Yves d’Udekem, M.D., Ph.D., as The Baier Family Distinguished Professor of Cardiac Surgery at Children’s National Hospital.

Dr. d’Udekem serves as chief of cardiac surgery at Children’s National Hospital, co-director of Children’s National Heart Institute, and professor of surgery and pediatrics, The George Washington University School of Medicine and Health Sciences.

About the award

Dr. d’Udekem joins a distinguished group of 41 Children’s National physicians and scientists who hold an endowed chair. Professorships at Children’s National support groundbreaking work on behalf of children and their families and foster new discoveries and innovations in pediatric medicine. These appointments carry prestige and honor that reflect the recipient’s achievements and donor’s forethought to advance and sustain knowledge.

Amy and Bret Baier, through their vision and generosity, are ensuring that Dr. d’Udekem and future holders of this professorship will launch bold, new initiatives to rapidly advance the field of pediatric cardiac surgery, elevate our leadership and improve the lifetimes of children with special hearts.

About the donors

The Baiers’ oldest son Paul was born with five congenital heart defects and needed open heart surgery when he was just 12 days old. He has since had three more open heart surgeries and countless procedures and visits to Children’s National. Dr. d’Udekem serves as Paul’s current heart surgeon.

Amy serves as Board Chair of Children’s National Hospital Foundation. Amy and Bret have served numerous times as co-chairs of the Children’s Ball, and Bret has emceed since 2008. They also are co-chairs for follow the leader, the hospital’s comprehensive campaign to fund bold initiatives in pediatric medicine. Children’s National is grateful for the Baiers’ generosity, leadership and commitment.

“I am forever grateful for the Baiers’ generosity and dedication to Children’s National,” said Kurt Newman, M.D., president and CEO of Children’s National Hospital. “With this endowed professorship, Yves will advance the field of pediatric cardiac surgery for kids with special hearts. I am honored to call Amy and Bret friends and partners in pediatric care.”

Addressing health equity issues through an app innovation competition

May 11, 2022

Children’s National Hospital launches The Health Equity in Research Hackathon — a team-based collaborative competition that empowers researchers to address health equity issues in the community through innovative apps. A panel of expert judges will select winning app ideas for full development, including finding grant opportunities, access to mentors and collaborators.

The big picture

“This Hackathon is a great chance for our research community to address larger issues related to advancing health equity within translational and clinical research,” said Patrick O’Keefe, administrative director for the Clinical and Translational Science Institute at Children’s National (CTSI-CN). “We are thrilled to see how people collaborate to create solutions for big problems that have traditionally slowed research and contributed to the vast inequities in health we see today.”

Additional details

The 2022 hackathon will be a two-part event. During Part I, slated for June 17, participants will gather in diverse teams to discuss and refine the selected app ideas. They will learn from technical and scientific experts and brainstorm app-based approaches to address health equity.

Each team will pitch their ideas to a panel of judges, and the winning app(s) will advance to Part II of the hackathon planned for Fall 2022, where app developers will build the selected apps.

“We encourage anyone at Children’s or George Washington University to submit an app idea – even if it is not fully formed — as long as they think it would help reduce health disparities through improving the research process,” said Lisa Guay-Woodford, M.D., director for Clinical and Translational Science Institute and Center for Translational Research at Children’s National. “We also hope researchers, staff and students who don’t have app ideas at this time will consider attending anyway to participate in the lively development process of the Hackathon.”

Anyone within the Children’s National and George Washington University research communities can submit an app idea for consideration. No app development experience is necessary to enter.

Why it matters

Health equity also means bringing the community into the research process. Thus, in part II, Children’s National will partner with high schools and universities in the area to incorporate voices who are often under-represented in the science and technology field.

“Our community is home to brilliant young minds at our local high schools and universities,” said Chaya Merrill, Dr.P.H., director for Child Health Data Lab at Children’s National. “We are excited to create an opportunity for them to work alongside experienced app builders – at the intersection of health equity and technology – by engaging in Part II of the Hackathon to build the winning apps!”

The hackathon will take place at Children’s Research and Innovation Campus in partnership with CTSI-CN and the Center for Translational Research.

The app idea submission deadline is on May 20, 2022, by 5pm. You may apply here. If you have questions about completing this submission, please email Patrick O’Keefe at pokeefe@childrensnational.org.

2022 Hackathon logo

Stress during pregnancy may hinder cognitive development

April 29, 2022

This is the first study to shed light on an important link between altered in-utero fetal brain development and the long-term cognitive development consequences for fetuses exposed to high levels of toxic stress during pregnancy.

Women’s elevated anxiety, depression and stress during pregnancy altered key features of the fetal brain, which subsequently decreased their offspring’s cognitive development at 18 months. These changes also increased internalizing and dysregulation behaviors, according to a new study by Children’s National Hospital published in JAMA Network Open. Researchers followed a cohort of 97 pregnant women and their babies. The findings further suggest that persistent psychological distress after the baby is born may influence the parent-child interaction and infant self-regulation.

This is the first study to shed light on an important link between altered in-utero fetal brain development and the long-term cognitive development consequences for fetuses exposed to high levels of toxic stress during pregnancy. While in the womb, the researchers observed changes in the sulcal depth and left hippocampal volume, which could explain the neurodevelopment issues seen after birth. Once they grow into toddlers, these children may experience persistent social-emotional problems and have difficulty establishing positive relationships with others, including their mothers. To further confirm this, future studies with a larger sample size that reflect more regions and populations are needed.

“By identifying the pregnant women with elevated levels of psychological distress, clinicians could recognize those babies who are at risk for later neurodevelopmental impairment and might benefit from early, targeted interventions,” said Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National and senior author of the study.

“By identifying the pregnant women with elevated levels of psychological distress, clinicians could recognize those babies who are at risk for later neurodevelopmental impairment and might benefit from early, targeted interventions,” said Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National and senior author of the study.

Regardless of their socioeconomic status, about one of every four pregnant women suffers from stress-related symptoms, the most common pregnancy complication. The relationship between altered fetal brain development, prenatal maternal psychological distress and long-term neurodevelopmental outcomes remain unknown. Studying in utero fetal brain development poses challenges due to fetal and maternal movements, imaging technology, signal-to-noise ratio issues and changes in brain growth.

All pregnant participants were healthy, most had some level of education and were employed. To quantify prenatal maternal stress, anxiety and depression, the researchers used validated self-reported questionnaires. Fetal brain volumes and cortical folding were measured from three-dimensional reconstructed images derived from MRI scans. Fetal brain creatine and choline were quantified using proton magnetic resonance spectroscopy. The 18-month child neurodevelopment was measured using validated scales and assessments.

This study builds upon previous work from the Developing Brain Institute led by Limperopoulos, which discovered that anxiety in pregnant women appears to affect the brain development of their babies. Her team also found that maternal mental health, even for women with high socioeconomic status, alters the structure and biochemistry of the developing fetal brain. The growing evidence underscores the importance of mental health support for pregnant women.

“We’re looking at shifting the health care paradigm and adopting these changes more broadly to better support moms,” said Limperopoulos. “What’s clear is early interventions could help moms reduce their stress, which can positively impact their symptoms and thereby their baby long after birth.”

Researcher to decipher how viruses affect the developing brain with nearly $1M NIH award

March 15, 2022

Zika virus in blood with red blood cells, a virus which causes Zika fever found in Brazil and other tropical countries.

The National Institutes of Health (NIH) awarded Children’s National Hospital nearly $1M of research support toward uncovering the specific cellular response that happens inside a developing brain once it is infected with a virus, including how the neuron gets infected, and how it dies or survives. The research is expected to gather critical information that can inform prenatal neuro-precision therapies to prevent or attenuate the effects of endemic and pandemic viruses in the future.

“We need to use all of the information we have from ongoing and past pandemics to prevent tomorrow’s public health crisis,” said Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National. “There is still here a whole lot to learn and discover. We could eventually — and this is the vision that’s inspiring us — prevent neurodevelopmental disorders before a baby is born by understanding more about the interaction between the virus, mother, fetus, and environment, among other factors.”

Different viruses, including HIV, CMV, Zika and rubella, injure the developing brain in very similar ways. This line of work was fostered first by the clinical research team led by Adre du Plessis, M.B.Ch.B., and Sarah Mulkey, M.D., supported by Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National.

The clinical research findings then led to the NIH support, which then inspired more basic science research. Fast forward to now, Kousa will study how Zika affects the human brain and extrapolate what is learned and discovered for a broader understanding of neurovirology.

The research program is supported by senior scientists and advisors, including Tarik Haydar, Ph.D., and Eric Vilain, M.D., Ph.D., both at Children’s National and Avindra Nath, M.D., at NIH, as well as other leading researchers at various U.S. centers.

“This is a team effort;” added Kousa, “I’m thankful to have a group of pioneering and seasoned researchers engaged with me throughout this process to provide invaluable guidance.”

Many viruses can harm the developing brain when they replicate in the absence of host defenses, including the gene regulatory networks responsible for the neuronal response. As a result, viral infections can lead to brain injury and neurodevelopmental delays and disorders such as intellectual disability, seizures that are difficult to treat, and vision or hearing loss.

The big picture

Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National.

The translational research supported by NIH with this award synergistically complements nationally recognized clinical research programs and ongoing prospective cohort studies at Children’s National to identify the full spectrum of neurodevelopmental clinical outcomes after prenatal Zika and other viral infections led by Dr. Mulkey and Roberta DeBiasi, M.D., M.S..

The award also builds upon strengths at the Children’s National Research & Innovation Campus, which is in proximity to federal science agencies. Children’s National experts from the Center for Genetic Medicine Research, known for pediatric genomic and precision medicine, joined forces with the Center of Neuroscience Research and the NIH-NINDS intramural research program to focus on examining prenatal and childhood neurological disorders.

Kousa received this competitive career development award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K08NS119882. The research content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The hold-up in the field

Many neurodevelopmental disorders are caused by endemic viruses, such as CMV, and by viral pandemics, including rubella as seen in the 1960s and Zika since 2015. By studying Zika and other prenatal viral infections, Kousa and team hope to gain deeper biological understanding of the viral effects toward developing therapies for anticipating, treating and preventing virally induced prenatal brain injury in the long-term future.

To date, little is known about how viruses affect developing neurons and, as a result, prenatal brain injury is not yet treatable. To bridge the gap towards prenatal neuro-precision therapies, the research explores how genes regulate neuronal developmental and viral clearance by innovatively integrating three systems:

Cerebral organoids, which illuminate how a neuron reacts to a viral infection
Pre-clinical models that link prenatal brain injury to postnatal neurodevelopmental outcomes
Populational genomics to identify human genetic risk or protective factors for prenatal brain injury

Given the scope and complexity of this issue, the international Zika Genetics Consortium, founded in 2015 by Kousa and a team of leading investigators across the world, provides critical samples and resources for the third arm of the research by performing comprehensive genomic analyses using sequencing data collected from diverse human populations throughout Central and South America, which are not as heavily sequenced as Western populations. Through partnerships with the Centers for Disease Control and Prevention and NIH, the consortium’s database and biorepository houses thousands of patient records and biospecimens for research studies to better understand how viruses affect the developing human brain.

“It is inspiring to imagine that, in the longer term, we could recognize early on the level of brain-injury risk faced by a developing fetus and have the tools to mitigate ensuing complications,” said Kousa. “What is driving this research is the vision that one day, brain injury could be prevented from happening before a baby is born.”

Children’s National uses HIFU to perform first ever non-invasive brain tumor surgery

February 9, 2022

Children’s National Hospital successfully performed the first-ever high-intensity focused ultrasound (HIFU) surgery on a pediatric patient with neurofibromatosis (NF). This is the youngest patient to undergo HIFU treatment in the world. Image provided by Insightec.

Children’s National Hospital successfully performed the first-ever high-intensity focused ultrasound (HIFU) surgery on a pediatric patient with neurofibromatosis (NF). This is the youngest patient to undergo HIFU treatment in the world. The advancement of children’s medical devices in the U.S. continues to significantly lag behind adult devices. This is why this milestone marks a significant advance in making pediatric surgery more precise and less invasive.

The hospital is offering this treatment to patients under an ongoing research clinical trial. Children’s National is one of the first pediatric hospitals in the nation to use HIFU for neuro-oncology patients. It’s also the first hospital in the world to use it to treat a pediatric patient with NF. NF is a condition that occurs in approximately 1 in 3,500 births and causes tumors to form in the brain, spinal cord and nerves.

“Using HIFU to treat our pediatric patients is a quantum leap towards non-invasive surgery for kids,” said Robert Keating, M.D., division chief of Neurosurgery and co-director of the HIFU program at Children’s National. “It’s exciting because the future is now here and it’s significantly better for our kids, in terms of non-invasive surgery with lower risk of complications and no exposure to radiation.”

Focused ultrasound (FUS) is a non-invasive therapeutic technology with the potential to transform the treatment of many medical disorders by using ultrasonic thermal energy to specifically target tissue deep in the body. The technology can treat without incisions or the need of radiation.

FUS, which has been used for adult clinical trials for many decades, can be delivered through high- or low-intensity focused ultrasound (LIFU). HIFU uses non-invasive therapy that uses focused ultrasound waves to thermally ablate a focal area of tissue. Children’s National will now use HIFU to treat low-grade type tumors located in difficult locations of the brain, such as hypothalamic hamartomas and pilocytic astrocytoma, as well as for movement disorders and epilepsy.

An alternative approach, LIFU uses lower levels of energy to disrupt the blood-brain barrier. Unlike medications, which often have difficulty crossing the blood-brain barrier, LIFU can transiently open the blood-brain barrier to chemotherapy. This may allow more effective treatment of tumors and offer opportunities to treat, for the first time, the entire extent of a malignant brain tumor.

“Having focused ultrasound technology as a tool and conducting clinical trials will allow our neurologists and oncologists to offer a non-invasive treatment option to many patients who suffer from neurological conditions,” said Hasan Syed, M.D., co-director of the HIFU center at Children’s National. “The milestone of performing this first HIFU procedure will lead the way to better understanding of the effect of this technology and provide patients with more options.”

At Children’s National, the HIFU program is being led by Dr. Keating and a multidisciplinary team, including clinicians and investigators from the Sheik Zayed Institute for Pediatric Innovation, radiology, oncology, surgery and orthopedics. In an effort to collaborate with the region’s adult hospitals, Children’s National will also treat adult patients on a selective basis who have movement disorders such as essential tremor and Parkinson’s. There is a scarcity of similar resources in the metro region. Many adult patients face one-year wait periods for treatment of their movement disorders, requiring many to travel out of state for treatment.

The LIFU program is scheduled to be operational in 2022. It will likely be the first in the U.S. to treat high-grade pediatric brain tumors with disruption of the blood-brain barrier and provide more effective routes for chemotherapy as well as potential immunotherapy and molecular approaches.

“The use of LIFU with microbubbles to open up the blood-brain barrier is an exciting, potentially game-changing approach for children with these tumors,” said Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National. “It should safely allow the blood-brain barrier to open and allow delivery of potentially life-saving personalized therapy to the tumor and spare the rest of the brain. It is the most exciting, new development in brain tumor therapy for these malignant midline tumors in the past 50 years.”

Children’s National continues to be a leader in pediatric HIFU use. In 2015, Children’s National doctors became the first in the U.S. to use MR-HIFU to treat pediatric osteoid osteoma – a benign, but painful bone tumor. Successful clinical trial results led to FDA approval in early 2021 for the use of the technology for this treatment. In 2020, the Focused Ultrasound Foundation also designated Children’s National as the first global pediatric Center of Excellence for using this technology to help patients with specific types of childhood tumors.

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

January 13, 2022

While pregnant women are at higher risk of severe illness, coronavirus can also trigger inflammatory and vascular responses in the placenta during critical periods of fetal development in symptomatic and asymptomatic cases.

Pregnant women should get vaccinated to minimize the detrimental health effects COVID-19 has on the placenta, the fetus and the newborn, states Roberta L. DeBiasi, M.D., M.S., division chief of Pediatric Infectious Diseases at Children’s National Hospital in an editorial published in The Journal of Infectious Diseases.

The editorial provides 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. The safety and efficacy of vaccination of pregnant women are also addressed.

While pregnant women are at higher risk of severe illness, the virus can also trigger inflammatory and vascular responses in the placenta during critical periods of fetal development in symptomatic and asymptomatic cases.

In this piece, Dr. DeBiasi comments on two related studies published in the same issue, Guan et al. and Shook et al., demonstrating pathologic findings in women’s placentas who had COVID-19 during pregnancy. Guan et al. published a detailed analysis of a stillbirth resulting from the delta variant infection during the third trimester.

“The authors present a highly plausible mechanism of stillbirth, namely that the virus-induced proinflammatory state ultimately led to placental abruption,” said Dr. DeBiasi.

Shook et al. presented a case series of pregnant women infected with the delta variant associated with stillbirth in two cases and one with severe neonatal illness.

“Taking the studies together, it’s evident that if a pregnant woman gets COVID-19 they’re at an increased risk of severe infection,” says DeBiasi. “They’re also at increased risk of adverse pregnancy outcomes, due to effects on the placenta, which may vary with specific circulating variants.”

Previous studies have documented that the placenta may be detrimentally affected by SARS-CoV-2 infection of the mother. However, maternal comorbidities such as hypertension, preeclampsia and gestational diabetes could also contribute to these findings.

“Despite these previous studies, the precise mechanisms of placental injury are still not clear and require further evaluation,” says Dr. DeBiasi. “Future research should include appropriate controls to better discern nonspecific versus SARS-CoV-2 specific effects and mechanisms of injury.”

Even though these potential risks exist, the vaccination rate among pregnant women is low. Dr. DeBiasi writes that recent publications have demonstrated vaccine efficacy and safety during pregnancy through programs that tracked the use in pregnant women. This data supports that COVID-19 vaccine offers another layer of protection to pregnant women since infants are not yet eligible for vaccination despite the fact that the youngest infants and children are among the most at risk among children for hospitalization.

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

January 4, 2022

Microscopic visual of a diseased muscle section. Credit: Daniel Bittel.

Children’s National Hospital experts developed a new pre-clinical gene therapy for a rare disorder, known as limb-girdle muscular dystrophy (LGMD) 2B, that addresses the primary cellular deficit associated with this disease. Using a single injection of a low dose gene therapy vector, researchers restored the ability of injured muscle fibers to repair in a way that reduced muscle degeneration and enhanced the functioning of the diseased muscle. The treatment was safe, attenuated fibro-fatty muscle degeneration, and restored myofiber size and muscle strength, according to the study published in the Journal of Clinical Investigation.

With an incidence of less than 1 in 100,000, LGMD2B is a rare disorder caused by a genetic mutation in a large gene called dysferlin. This faulty gene leads to muscle weakness in the arms, legs, shoulder and pelvic girdle. Affected children and adults face trouble walking, climbing stairs and getting out of chairs. Individuals typically lose the ability to walk within years after the onset of symptoms, and often need assistance with everyday tasks such as showering, dressing and transferring.

This study described a new approach that avoids the need for packaging a large gene, like dysferlin, or giving a large vector dose to target the muscles, which are bottlenecks faced in ongoing gene therapy efforts aimed at muscular dystrophies.

“Currently, patients with LGMD2B have no gene or drug-based therapies available to them, and we are amongst the few centers developing therapeutic approaches for this disease,” said Jyoti K. Jaiswal, M.Sc. Ph.D., senior investigator of the Center for Genetic Medicine Research at Children’s National. “We are working to further enhance the efficacy of this approach and perform a longer-term safety and efficacy study to enable the clinical translation of this therapy.”

The genetic defect in dysferlin that is associated with LGMD2B causes the encoded protein to be truncated or degraded. This hinders the muscle fiber’s ability to heal, which is required for healthy muscles. In recessive genetic disorders, like LGMD2B, common pre-clinical gene therapy approaches usually target the mutated gene in the muscle, making them capable of producing the missing proteins.

“The large size of the gene mutated in this disease, and impediments in body-wide delivery of gene therapy vectors to reach all the muscles, pose significant challenges for developing gene therapies to treat this disease,” said Jaiswal.

To overcome these challenges, the researchers found another way to slow down the disease’s progression. The authors built upon their previous discovery that acid sphingomyelinase (hASM) protein is required to repair injured muscle cells. In this current work, the research team administered a single in vivo dose of an Adeno-associated virus (AAV) vector that produces a secreted version of hASM in the liver, which then was delivered to the muscles via blood circulation at a level determined to be efficacious in repairing LGMD2B patient’s injured muscle cells.

“Increased muscle degeneration necessitates greater muscle regeneration, and we found that improved repair of dysferlin-deficient myofibers by hASM-AAV reduces the need for regeneration, causing a 2-fold decrease in the number of regenerated myofibers,” said Daniel Bittel, D.P.T., PhD., research postdoctoral fellow of the Center for Genetic Medicine Research at Children’s National and a lead author of this study.

Sreetama Sen Chandra, Ph.D., who was a research postdoctoral fellow at Children’s National at the time of this study and served as co-lead author, also added that “these findings are also of interest to patients with Niemann-Pick disease type A since the pre-clinical model for this disease also manifests poor sarcolemma repair.”

Children’s National researchers of the Center for Genetic Medicine Research and the Rare Disease Institute (RDI) are constantly pursuing high-impact opportunities in pediatric genomic and precision medicine. Both centers combine its strengths with public and private partners, including industry, universities, federal agencies, start-up companies and academic medical centers. They also serve as an international referral site for rare disorders.

Gene therapy Schematic. Credit: Daniel Bittel.

Study with largest cohort in the Western world sheds light on Epstein-Barr virus

November 23, 2021

Epstein-Barr virus is a member of the herpes family and it spreads primarily through saliva.

Children’s National Hospital experts provided a contemporary description of the epidemiology, clinical presentation and management of chronic active Epstein-Barr virus (CAEBV), shedding light on this very rare disease. The paper, published in Blood Advances, assessed 57 patients outside of Asia — the biggest international retrospective cohort study published in the Western world.

Epstein-Barr virus is a member of the herpes family and it spreads primarily through saliva. Once a person is infected with Epstein-Barr virus, the immune system will control the infections, but the virus lies in a dormant state in the patient’s B Cells. However, in some patients, there is a failure of the body to control the infection, and the virus is found inside the patient’s T and/or NK cells. These rare patients are diagnosed with CAEBV. The hallmark of the disease is proliferation of Epstein-Barr virus-infected T or NK cells that infiltrate tissues, leading to end-organ damage. Patients most often experience fevers, hepatosplenomegaly, liver inflammation, cytopenias and lymphoproliferation that may progress to lymphoma.

Given it is most prevalent in Asia, little is known about the disease in the Western world. There has only been one published paper regarding the outcomes of patients in the U.S., which included 19 patients amassed over 28 years, and was published a decade ago.

Multiple treatments have been attempted to control the disease, but none have resulted in consistent remission. Historically, the consensus is to use steroids and/or antiviral drug in combination with proteasome inhibitor agents. In some cases, clinicians also use cytotoxic chemotherapy to reduce disease burden and improve the patient’s condition before HSCT. Still, this approach is limited because most patients die due to the progression of their disease despite these interventions.

Ultimately, most of these patients are referred for allogeneic hematopoietic stem cell transplantation (HSCT), which is the only known curative therapy for CAEBV. However, the best approach to control disease prior to HSCT, as well as the optimal conditioning regimen, are unknown.

“For the first time in many years, we provide insight on contemporary treatment options to consider for patients with CAEBV, as well as identifying risk factors for worse outcomes,” said Blachy Dávila Saldaña, M.D., blood and marrow transplant specialist at Children’s National and lead author of the study. “HSCT is curative, but patients need to be considered prior to the evolution of more advanced disease, particularly lymphoma. We also provide a new platform that will inform research on new interventions and therapies for this population.”

“CAEBV remains a challenging disorder to treat, especially once severe complications develop,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National. “However, our data suggests that T cell modulating therapies may enhance disease control, and future studies should address this question in a controlled setting.”

Future steps also include performing genetic studies to identify those at risk of developing the disease, and developing new platforms for treatment, including checkpoint inhibitors and cytotoxic lymphocyte therapies (CTL’s), which is a form of adoptive immunotherapy that employs virus-specific T cells.

The cohort includes patients treated in CNH and multiple institutions around the world, including Texas Children’s and the National Institutes of Health. “This work was only possible through our collaborative research in anti-EBV cellular therapies,” said Dr. Dávila.

Personalized T cell immunotherapy for brain tumors closer to becoming reality

November 18, 2021

Children’s National Hospital experts developed a new approach that discovered unique proteins in an individual tumor’s cells, which then helped scientists generate personalized T cells to target and kill tumors.

Children’s National Hospital experts developed a new approach that discovered unique proteins in an individual tumor’s cells, which then helped scientists generate personalized T cells to target and kill tumors, according to a pre-clinical study published in Nature Communications.

This effort is the first to create a new workflow for neoantigen identification that incorporates both genetic sequencing and protein identification to create a personalized treatment for medulloblastoma in children, a common malignant brain tumor. Given these promising findings, the researchers are now designing a phase I clinical trial slated to open in 12-18 months.

“This work is an incredibly exciting advancement in personalized medicine. It will allow us to treat patients with a novel T cell therapy that is developed for each individual patient to specifically attack and kill their tumor,” said Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National and co-author on the paper. “This treatment will offer a potential option for children with hard-to-treat brain tumors for which all other therapeutic options have been exhausted.”

Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research at Children’s National and co-senior author on the paper.

First, the researchers sequenced the DNA of small tissue samples while studying its complete set of proteins that influence cancer biology — also named a “low-input proteogenomic approach” by the authors. After analyzing the empirical data, which shies away from the commonly used predictive models, the researchers developed a T cell immunotherapy that targets the tumor’s unique proteins and allows the T cells to distinguish between healthy cells and tumor cells. This means that Rivero-Hinojosa et al. managed to merge two research fields, proteogenomics and immunotherapy, and lay the groundwork for personalized, targeted T cell therapies to treat children with brain tumors.

“Neoantigen discovery techniques have either been dependent upon in silico prediction algorithms or have required a significant amount of tumor tissue, making them inappropriate for most brain tumors,” said Brian Rood, M.D., medical director of Neuro-oncology and the Brain Tumor Institute at Children’s National. “This neoantigen identification pipeline creates a new opportunity to expand the repertoire of T cell-based immunotherapies.”

Tumor cells have damaged DNA that create mutations during the repair process because they do not do a good job at maintaining their DNA fidelity. The repairs therefore create aberrant DNA that codes for proteins that were never intended by the genetic code and, consequently, they are unique to the individual’s tumor cells.

Brian Rood, M.D., medical director of Neuro-oncology and the Brain Tumor Institute at Children’s National and co-senior author on the paper.

“We developed a new filtering pipeline to remove non-annotated normal peptides. Targeting antigens that are completely specific to the tumor, and expressed nowhere else in the body, will potentially increase the strength of tumor antigen-specific T cell products while decreasing the toxicity,” said Samuel Rivero-Hinojosa, Ph.D., staff scientist at Children’s National and first author of the study.

Once the experts identified these unique peptides, they used them to select and expand T cells, which showed specificity for the tumor specific neoantigens and the ability to kill tumor cells. The next step is to conduct a clinical trial in which a patient’s own T cells are trained to recognize their tumor’s unique neoantigens and then reinfused back into the patient.

From an immunotherapy standpoint, tumor specificity is important because when clinicians treat patients with T cell therapies, they want to make sure that the T cells directly target and kill the tumor and will not cause devastating harm to healthy cells. This paper demonstrated that it may be possible to create a better efficacy and safety margin with this new approach.

In the past five years, under the leadership of Dr. Bollard, the Center for Cancer and Immunology Research at Children’s National has advanced the scientific knowledge in preclinical and clinical settings. The center discovered a signaling pathway that can be hijacked to prevent brain tumor development, and further advanced translational research with several key first-in-human studies that utilized novel cell therapies to treat cancer and life-threatening viral infections.

Children’s National Rare Disease Institute named a Center of Excellence

November 4, 2021

RDI, which includes the largest clinical group of pediatric geneticists in the nation, focuses on developing the clinical care field of more than 8,000 rare diseases currently recognized and advancing the best possible treatments for children with these diseases.

The Rare Disease Institute (RDI) at Children’s National Hospital announced its designation as a NORD Rare Disease Center of Excellence, joining a highly select group of 31 medical centers nationwide. This new, innovative network seeks to expand access and advance care and research for rare disease patients in the United States. The program is being led by the National Organization for Rare Disorders (NORD), with a goal to foster knowledge sharing between experts across the country, connect patients to appropriate specialists regardless of disease or geography, and to improve the pace of progress in rare disease diagnosis, treatment and research.

“Children’s National has worked closely with NORD to move this program forward and is very proud to be amongst the first group of recognized centers,” said Marshall Summar, M.D., chief of the Division of Genetics and Metabolism and the director of RDI at Children’s National. “This is a recognition of the institutional efforts, as we take care of patients with the rare disease and help set the standard for the field.”

RDI, which includes the largest clinical group of pediatric geneticists in the nation, focuses on developing the clinical care field of more than 8,000 rare diseases currently recognized and advancing the best possible treatments for children with these diseases.

In February 2021, RDI became the first occupant of the new Children’s National Research & Innovation Campus, a first-of-its-kind pediatric research and innovation hub. The campus now also houses the Center for Genetic Medicine Research, and together researchers are constantly pursuing high-impact opportunities in pediatric genomic and precision medicine. Both centers combine its strengths with public and private partners, including industry, universities, federal agencies, start-up companies and academic medical centers. They also serve as an international referral site for rare disorders.

People living with rare diseases frequently face many challenges in finding a diagnosis and quality clinical care. In establishing the Centers of Excellence program, NORD has designated clinical centers across the U.S. that provide exceptional rare disease care and have demonstrated a deep commitment to serving rare disease patients and their families using a holistic, state of the art approach.

“Right now, far too many rare diseases are without an established standard of care. The Centers of Excellence program will help set that standard – for patients, clinicians, and medical centers alike,” said Ed Neilan, chief scientific and medical officer of NORD. “We are proud to announce Children’s National as a NORD Rare Disease Center of Excellence and look forward to their many further contributions as we collectively seek to improve health equity, care and research to support all individuals with rare diseases.”

Each center was selected by NORD in a competitive application process requiring evidence of staffing with experts across multiple specialties to meet the needs of rare disease patients and significant contributions to rare disease patient education, physician training and research.

Q&A with Dr. Javad Nazarian on his upcoming work on low-grade gliomas

October 28, 2021

Supported by the Gilbert Family Foundation, Dr. Nazarian’s return is part of a special research program within the Gilbert Family Neurofibromatosis Institute that focuses on NF1 research.

Javad Nazarian, Ph.D., M.Sc., associate professor of Pediatrics at George Washington University and professor at the University of Zurich, has expanded his research group at Children’s National to focus on Neurofibromatosis type 1 (NF1) transformed low-grade gliomas (LGGs). Dr. Nazarian will apply his expertise from establishing a successful DIPG (diffuse intrinsic pontine glioma) and DMG (diffuse midline glioma) program in Zurich Switzerland and previously at Children’s National.

In addition to his continued research in Zurich, as a principal investigator at the Department of Genomics and Precision Medicine at Children’s National Dr. Nazarian plans on aggregating his knowledge to the new research and work spearheaded at Children’s National. As one of the first research teams to move to the Children’s National Research & Innovation Campus, Dr. Nazarian’s group is excited to use the opportunity to establish cutting-edge and clinically translational platforms.

Supported by the Gilbert Family Foundation, Dr. Nazarian’s return is part of a special research program within the Gilbert Family Neurofibromatosis Institute that focuses on NF1 research. This research includes associated gliomas with a special emphasis on NF1-associated transformed anaplastic LGGs. His team will develop new avenues of research into childhood and young adult NF-associated LGGs with a special emphasis on transformed high-grade gliomas.

Dr. Nazarian is excited for what’s to come and his goals are clear and set. Here, Dr. Nazarian tells us more about his main objectives and what it means for the future of pediatric neuro-oncology care at Children’s National.

What excites you most about being back at Children’s National?

I have received most of my training at Children’s National, so this is home for me. Being one of the nation’s top children’s hospitals gives a unique advantage and ability to advocate for childhood diseases and cancers. It is always exciting to play a part in the vision of Children’s National.

What are some of the lessons learned during your time working in Zurich? And how do you think these will compliment your work at Children’s National?

We developed a focused group with basic research activities intertwined with clinical needs. The result was the launch of two clinical trials. I also helped in developing the Diffuse Midline Glioma-Adaptive Combinatory Trial (DMG-ACT) working group that spans across the world with over 18-member institutions that will help to design the next generation clinical trials. I will continue leading the research component of these efforts, which will have a positive impact on our research activities at Children’s National.

How does your work focusing on low-grade gliomas formulating into high-grade gliomas expand and place Children’s National as a leader in the field?

Scientifically speaking, transformed LLGs are very intriguing. I became interested in the field because these tumors share molecular signatures similar to high-grade gliomas (HGGs). Our team has done a great job at Children’s National to develop tools – including biorepositories, avatar models, drug screening platforms, focused working groups, etc. – for HGGs. We will apply the same model to transformed LGGs with the goal of developing biology-derived clinical therapeutics for this patient population.

How will this work support families and patients seeking specific neuro-oncology care?

We will develop new and high thruput tools so that we can better study cancer formation or transformation. These tools and platforms will allow us to screen candidate drugs that will be clinically effective. The main focus is to accelerate discovery, push drugs to the clinic, feed information back to the lab from clinical and subsequently design better therapies.

You are one of the first scientists to move to the Children’s National Research & Innovation Campus. What are some of the valuable changes or advancements you hope to see as a result of the move?

The campus will provide high-end facilities, including cutting-edge preclinical space, and allow for team expansion. The close proximity to Virginia Tech will also provide an environment for cross-discipline interactions.

Anything else you think peers in your field should know about you, the field or our program?

The team at Children’s National includes Drs. Roger Packer and Miriam Bornhorst. Both have provided constant clinical support, innovation and clinical translation of our findings. I look forward to working with them.

Cardiopulmonary bypass may cause significant changes to developing brain and nerve cells

October 26, 2021

brain network illustration

Cardiopulmonary bypass, more commonly known as heart-and-lung bypass, has some unique impacts on the creation and growth of brain cells in the area of a child’s brain called the subventricular zone (SVZ), according to a study in the Annals of Neurology. The SVZ is a critical area for the growth and migration of neurons and nerve cells called neuroblasts, both of which ultimately contribute to the proper development of key brain structures and functions during the early years of life.

The findings, from a study conducted in the Cardiac Surgery Research Laboratory at Children’s National Hospital, provide new insight into the cellular impacts of the cardiopulmonary bypass machine on brain growth and development for newborn infants with congenital heart disease. They will have an important role in the refinement of strategies to help protect the fragile brains of children who require lifesaving cardiac surgery with cardiopulmonary bypass immediately after birth.

Specifically, the research team found that during cardiopulmonary bypass:

Creation of neurons (neurogenesis) in the neonatal and infant subventricular zone is altered.
Migration of nerve cells, called neuroblasts, to the frontal lobe is potentially disrupted.
Changes to the growth and movement of neurons in the SVZ are prolonged.
Cortical development and expansion is impaired.
Specific types of neurons found only in the brain and spinal cord, called interneurons, are also affected.

The study uses an innovative pre-clinical model of the developing brain that is more anatomically and physiologically similar to human neonates and infants than those used in prior studies and in most neurological laboratory-based research.

Cardiopulmonary bypass is one of several key factors thought to cause children with congenital heart disease to sometimes demonstrate delays in the development of cognitive and motor skills. These disabilities often persist into adolescence and adulthood and can ultimately represent long-term neurocognitive disabilities. It is also believed that genetic factors, abnormal blood flow to the brain while in utero or low cardiac output after surgical procedures on the heart may contribute to these challenges.

“Unraveling cellular and molecular events during surgery using this preclinical model will allow us to design therapeutic approaches that can be restorative or reparative to the neurogenic potential of the neuronal stem precursor cells found in the subventricular zone of the neonatal or infant brain,” says Nobuyuki Ishibashi. M.D., Foglia-Hills Professor of Pediatric Cardiac Research, director of the Cardiac Surgery Research Laboratory at Children’s National and senior author on the study. “In particular, previous studies in our laboratory have shown improvement in the neurogenic activities of these precursor cells when they are treated with mesenchymal stromal cells (MSCs).”

The findings from this study further support the work already underway in the NIH-funded MeDCaP clinical trial for neonates and infants undergoing cardiac surgery using the cardiopulmonary bypass machine. That trial uses the heart and lung machine itself to deliver MSCs directly into the main arteries that carry blood to the brain.

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