microglia cells damage the myelin sheath of neuron axons

Katrina Adams, Ph.D., awarded fellowship to help restore functions in MS patients

microglia cells damage the myelin sheath of neuron axons

Multiple sclerosis is a demyelinating disease in which the insulating covers of nerve cells are damaged. Microglia cells (orange) attack the oligodendrocytes that form the insulating myelin sheath around neuron axons, leading to the destruction of the myelin sheath and to the loss of nerve function.

For her contributions to Multiple Sclerosis (MS) research, Katrina Adams, Ph.D., postdoctoral researcher at Children’s National Hospital, received the career transition fellowship from The National Multiple Sclerosis Society. The $600,000 fellowship will support a two-year period of advanced postdoctoral training in MS research and the first three years of research support in a new faculty appointment.

MS symptoms, including vision loss, pain, fatigue and reduced motor coordination, result from the demyelination of neuronal axons that transport critical information across the brain and spinal cord. Demyelination is the loss of myelin protein, which is normally produced by oligodendrocyte cells.

In the healthy brain, oligodendrocytes repair demyelinated areas by replacing damaged or lost myelin in a process called remyelination. Recent evidence has shown that oligodendrocytes display differences in their molecular and functional properties. One source of new oligodendrocytes in the adult brain is neural stem cells, which have been shown to generate oligodendrocytes that contribute to remyelination.

“The goal of this project is to determine whether neural stem cell-derived oligodendrocytes are distinct from other oligodendrocytes, both in the healthy brain and in MS,” said Adams. “I aim to understand the molecular mechanisms that regulate generation of oligodendrocytes from neural stem cells, with the goal of identifying signals that could be targeted in MS patients to promote remyelination.”

Remyelination is very limited in MS patients and current therapies for MS have very little impact on promoting remyelination.

This study will take advantage of the state-of-the-art facilities for single-cell analysis, transcriptomics, microscopy, and animal research in Children’s Research Institute at Children’s National. Adams also added that her postdoctoral mentor, Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the DC-IDDRC, has renowned expertise in glial biology, animal models of MS and white matter injury.

“This research will be the first to directly compare neural stem cell-derived oligodendrocytes with other resident oligodendrocytes in MS brain samples,” said Adams. “The results of this study will provide critical insight into the role that neural stem cells play in repair of MS demyelinated lesions.”

Adams received her doctorate in molecular biology from the University of California, Los Angeles where she used pluripotent stem cells to study motor neuron development. She currently investigates signaling pathways that regulate neural stem and progenitor cell maintenance and differentiation in the developing postnatal and adult brain, with a focus on the Endothelin-1 pathway. She is interested in understanding how stem and progenitor cells respond to disease or injury, such as in Multiple Sclerosis, with the hope of identifying new therapeutic targets.

doctor checking boy for concussion

NINDS awards $10 million for pediatric concussion research

doctor checking boy for concussion

Every year, more than 3 million Americans are diagnosed with concussions. Symptoms continue to plague 30 percent of patients three months after injury — adolescents face an even higher risk of delayed recovery.

The National Institute of Neurological Disorders and Stroke has awarded a $10-million grant to the Four Corners Youth Consortium, a group of academic medical centers studying concussions in school-aged children. Led in part by the Safe Concussion Outcome Recovery and Education (SCORE) program at Children’s National Hospital, the project is named Concussion Assessment, Research and Education for Kids, or CARE4Kids.

Researchers will use advanced brain imaging and blood tests to explore biological markers—changes in blood pressure, heart rate and pupil reactivity—that could predict which children will develop persistent symptoms after concussion. The five-year CARE4Kids study will enroll more than 1,300 children ages 11-18 nationwide.

The five-year study will be led by Gerard Gioia, Ph.D., division chief of Neuropsychology at Children’s National Hospital, Frederick Rivara, M.D., M.P.H., at Seattle Children’s Center for Child Health, Behavior and Development and University of Washington’s Medicine’s Department of Pediatrics, and Dr. Chris Giza at University of California, Los Angeles (UCLA).

“We will be gathering innovative data to help answer the critical question asked by every patient: ‘When can I expect to recover from this concussion?’” said Dr. Gioia. “We have a great team and are excited to have been selected to study this important issue.”

Christopher G. Vaughan, Psy.D., neuropsychologist, and Raquel Langdon, M.D., neurologist, both at Children’s National, will join Dr. Gioia as principal investigators of the study at this site.

Every year, more than 3 million Americans are diagnosed with concussions. Symptoms continue to plague 30 percent of patients three months after injury—adolescents face an even higher risk of delayed recovery. Chronic migraine headaches, learning and memory problems, exercise intolerance, sleep disturbances, anxiety and depressed mood are common.

“Providing individualized symptom-specific treatments for youth with a concussion has been a longstanding aim of the SCORE program,”Dr. Vaughan said. “This project will lead to a better understanding of the specific markers for which children may have a longer recovery. With this knowledge, we can start individualized treatments earlier in the process and ultimately help to reduce the number of children who experienced prolonged effects after concussion.”

The grant was announced on September 9, 2021.

In Washington, D.C., an estimated 240 children ages 11 to 18, will participate in the study.

The study will unfold in two phases. The first part will evaluate children with concussion to identify a set of biomarkers predictive of persistent post-concussion symptoms. To validate the findings, the next stage will confirm that these biomarkers accurately predict prolonged symptoms in a second group of children who have been diagnosed with concussion. The goal is to develop a practical algorithm for use in general clinical practice for doctors and other health professionals caring for pediatric patients.

Institutions currently recruiting patients for the study include Children’s National Hospital, UCLA Mattel Children’s Hospital, Seattle Children’s, the University of Washington, University of Rochester, University of Texas Southwestern Medical Center and Wake Forest School of Medicine. Indiana University, the National Institute of Nursing Research, University of Arkansas, University of Southern California and the data coordinating center at the University of Utah are also involved in the project.

Earlier research conducted by the Four Corners Youth Consortium that led to this project was funded by private donations from Stan and Patti Silver, the UCLA Steve Tisch BrainSPORT Program and the UCLA Easton Clinic for Brain Health; Children’s National Research Institute; as well as from the Satterberg Foundation to Seattle Children’s Research Institute; and an investment from the Sports Institute at UW Medicine.

3d render of brain form

LEND program to support physicians with interdisciplinary training for NDD and ASD

3d render of brain form

In a time with dearth of specialties, LEND will train allied health professionals, parent advocates and self-advocates, provide continuing education and technical assistance, research and consultation while preparing professionals for leadership roles in the provision of health and related care.

A new program at Children’s National Hospital, known as The Leadership Education in Neurodevelopmental and Other Related Disabilities (LEND CN), will provide interdisciplinary training to enhance clinical expertise and leadership skills while reducing the shortage of medical specialists — a hurdle also present nationwide. Participating institutions such as Children’s National Hospital, Howard University and University of the District of Columbia will enhance the care for children and families with neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD).

The program seeks to improve the health of infants, children and adolescents with or at risk for NDD and related disabilities. LEND CN will also prepare future leaders in this space that offer a comprehensive support tailored to a child’s specific condition.

“There are very few opportunities for training a broad multidisciplinary team to work with and provide leadership in the neurodevelopmental and autism space,” said Andrea Gropman, M.D., neurodevelopmental pediatrics and neurogenetics division chief at Children’s National Hospital and principal investigator of the LEND CN program. “This grant funding will allow the LEND CN leadership and curriculum team to develop innovative training and leverage community resources, universities and institutions to provide a broad, diverse and inclusive training.”

The Health Resources and Services Administration (HRSA) awarded the program with $2,200,000. The funding will help develop, implement, evaluate and innovate the curriculum and experiential activities of LEND CN. These efforts will be led by Dr. Gropman and Anne Pradella Inge, Ph.D., clinical director of the Center for Autism Spectrum Disorders at Children’s National Hospital and LEND educational content director.

In a time with dearth of specialties, LEND will train allied health professionals, parent advocates and self-advocates, provide continuing education and technical assistance, research and consultation while preparing professionals for leadership roles in the provision of health and related care.

“We have a broad multidisciplinary team of specialists in developmental pediatrics, neuropsychology, speech and hearing, and other allied health specialists,” Dr. Gropman said, adding that Children’s National is uniquely positioned to participate in this grant opportunity. “This grant is exciting because it allows us to take advantage of the full potential the D.C. area has to offer to establish comprehensive and individualized training.”

Many of the trainees of this program remain local and in the field of developmental disabilities and autism, while many others also have risen to leadership positions. Some who have completed the program return as LEND educators to the next generation of trainees, proving the many doors this program can open for those seeking a career in neurodevelopmental pediatrics and work that intersects with developmental disabilities and their families.

illustration of Research & Innovation Campus

NIH awards $6.7M to build additional lab space at Children’s National Research & Innovation Campus

Children’s National Hospital today announced a $6.7 million award from the National Institute of Health (NIH) for the new Children’s National Research & Innovation Campus (RIC). The funds will help transform a historic building on the former site of Walter Reed Army Medical Center into new research labs. The NIH construction grant marks the first secured grant funding for Phase II of the campus project, signaling continued momentum for the first-of-its-kind pediatric research and innovation hub.

The funding was announced as D.C. Mayor Muriel Bowser, D.C. Deputy Mayor for Planning and Economic Development John Falcicchio and D.C. Council Chair Phil Mendelson took their first tour of the already-renovated Phase I of the RIC. The campus began opening in early 2021 and brings together Children’s National with top-tier research and innovation partners: Johnson & Johnson Innovation – JLABS @ Washington, DC and Virginia Tech. They come together with a focus on driving discoveries and innovation that will save and improve the lives of children.

“This NIH award is the latest confirmation that we are creating something very special at the Children’s National Research & Innovation Campus,” said Kurt Newman, M.D., president and CEO of Children’s National. “Only the D.C. region can offer this proximity to federal science agencies and policy makers. When you pair our location with these incredible campus partners, I know the RIC will be a truly transformational space where we develop new and better ways to care for kids everywhere.”

The campus is an enormous addition to the BioHealth Capital Region, the fourth largest research and biotech cluster in the U.S., with the goal of becoming a top-three hub by 2023. The RIC exemplifies the city’s commitment to building the partnerships necessary to drive discoveries, create jobs, promote economic growth, treat underserved populations, improve health outcomes, and keep D.C. at the forefront of innovation and change.

“We are proud to officially welcome the Children’s National Research & Innovation Campus to the District and to the Ward 4 community,” said Mayor Bowser, after touring the campus. “This partnership pairs a world-class hospital with a top university and a premier business incubator – right here in the capital of inclusive innovation. Not only will our community benefit from the jobs and opportunities on this campus, but the ideas and innovation that are born here will benefit children and families right here in D.C. and all around the world.”

The NIH grant funding announced today will go toward the expansion and relocation of the DC Intellectual and Developmental Disabilities Research Center (DC-IDDRC). This research center will increase the efforts to improve the understanding and treatment of children with developmental disabilities, including autism, cerebral palsy, epilepsy, inherited metabolic disorders and intellectual disability.

The space where the new lab will be built used to be the Armed Forces Institute of Pathology Building, a portion of the Walter Reed Army Medical Center. The site closed and Children’s National secured 12 acres in 2016, breaking ground on Phase I construction in 2018.

The new space will offer highly cost-effective services and unique state-of-the-art research cores that are not available at other institutions, boosting the interdisciplinary and inter-institutional collaboration between Children’s National, George Washington University, Georgetown University and Howard University. Investigators from the four institutions will access the center, which includes hoteling laboratory space for investigators whose laboratories are not on-site but are utilizing the core facilities — Cell and Tissue Microscopy, Genomics and Bioinformatics, and Inducible Pluripotent Stem Cells.

“While we have explored outsourcing some of these cores, especially genomics, we found that expertise, management, training and technical support needed for pediatric research requires on-site cores,” said Vittorio Gallo, Ph.D., interim chief academic officer, interim director of the Children’s National Research Institute, and principal investigator for the DC-IDDRC. “The facility is designed to support pediatric studies that are intimately connected with our community. We operate in a highly diverse environment, addressing issues of health equity through research.”

The RIC provides graduate students, postdocs and trainees with unique training opportunities, expanding the workforce and talent of new investigators in the D.C. area. Young investigators will have job opportunities as research assistants and facility managers as well. The new labs will support these researchers so they can tackle pressing questions in pediatric research by integrating pre-clinical and clinical models.

Phase II will place genetic and neuroscience research initiatives of the DC-IDDRC at the forefront to treat a variety of pediatric developmental disorders. Other Children’s National research centers will also benefit from this additional space. The clinical and research campuses will be physically and electronically integrated with new informatics and video-communication systems.

The total projected cost of Phase II is $180 million, with design and construction to take up to three years to complete once started.

illustration of Research & Innovation Campus

Phase II will place genetic and neuroscience research initiatives of the DC-IDDRC at the forefront to treat a variety of pediatric developmental disorders. Other Children’s National research centers will also benefit from this additional space. The clinical and research campuses will be physically and electronically integrated with new informatics and video-communication systems.

boy with a chromosomal developmental disability.

NIH award will support intellectual and developmental disabilities research at Children’s National

boy with a chromosomal developmental disability.

Children’s National Hospital announces a $7 million award from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to support the DC Intellectual and Developmental Disabilities Research Center (DC-IDDRC).

Children’s National Hospital announces a $7 million award from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to support the DC Intellectual and Developmental Disabilities Research Center (DC-IDDRC). Through this award, the DC-IDDRC will enhance the recruitment and training of investigators, generate innovation and promote transdisciplinary research to facilitate the development, implementation and dissemination of new diagnostic and therapeutic advances for the care of individuals with intellectual and developmental disabilities.

The DC-IDDRC, led by Children’s National in partnership with George Washington University, Howard University and Georgetown University, is one of only 14 IDDRCs in the United States funded by NICHD. This long standing NICHD program supports researchers whose goals are to advance understanding of a variety of conditions and topics related to intellectual and developmental disabilities.

“Children’s National cares for one of the largest cohorts of children with developmental disabilities in the U.S. — which uniquely positions us to lead the way in both care and research of developmental disabilities in young children,” said Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the DC-IDDRC.

The research strategy for this period will address three key areas: neural development and neurodevelopmental disorders, fetal and neonatal brain injury and genetic disorders by leveraging the core facilities and core innovation — including the Genomics and Bioinformatics Core, Cell and Tissue Microscopy Core, Neuroimaging Core, Clinical Translational Core and Neurobehavioral Evaluation Core.

“In spite of tremendous advances in our understanding of how abnormalities in brain development cause neurodevelopmental disorders and developmental disabilities, integrated knowledge in all these areas of research is still lacking. In particular, it is still unknown how specific genetic defects and cellular abnormalities result in behavioral phenotypes,” said Gallo.

One in six children suffers from a chronic, complex neurodevelopmental disability — conditions such as intellectual disability, learning disability, attention deficit hyperactivity disorder, autism spectrum disorder, cerebral palsy and Down syndrome. For 20 years, the DC-IDDRC has been a home for researchers from different specialties and different institutions to discover new therapies and treatments for children with these types of neurodevelopmental disabilities.

“The DC-IDDRC promises to be a great vehicle to spawn new research and collaborative networks for D.C. area investigators,” said Chandan Vaidya, Ph.D., vice provost for faculty and professor at Georgetown University. “We will be examining whether a behavioral intervention to enhance self-regulation in adolescents with Autism changes how they learn and use computational modeling to understand learning strategy and identify associated changes in the brain using functional magnetic resonance imaging.”

The robust relationships and spirit of cooperation built over two decades of collaboration have laid a strong groundwork for the establishment of the expansive post-doctoral training program and continuous growth of the research programs within the DC-IDDRC. Gallo continues his efforts in expanding access to these programs and building a sustainable pipeline of young scholars from diverse backgrounds. The partnership between Children’s National and Howard University continues to play a crucial role in these goals.

The DC-IDDRC continues to work toward translating research findings into novel approaches and personalized treatments for people with developmental disabilities and their caregivers. This work will be amplified when the DC-IDDRC moves into the expanded facility at the Children’s National Research & Innovation Campus, which houses startup incubator programs and other support for device innovation.

coronavirus

One-half of MIS-C patients at a single center experienced heart complications

coronavirus

A single center study of patients with multisystem inflammatory disease in children (MIS-C) found that half of children diagnosed with MIS-C had a heart complication as part of the disease. The study collected and analyzed data from 39 cases of MIS-C at Children’s National Hospital in 2020. MIS-C is a pediatric disease that has been linked to SARS-CoV-2, the virus that causes COVID-19.

The study’s findings appear in the journal Cardiology of the Young. The authors aimed to describe the type and frequency of cardiac complications in children with MIS-C while also outlining the disease’s short-term progression. They also hoped to better understand the demographics, clinical and laboratory findings, as well as the therapeutic successes for children with cardiac complications from MIS-C.

“While half of all children at our hospital diagnosed with MIS-C did experience a cardiac complication, it’s important to note that almost all of them (84%) also fully recovered from that cardiac complication within 50 days of diagnosis,” says Ashraf Harahsheh, M.D., director of Quality Outcomes in Cardiology at Children’s National Hospital, who led the study. “We were also able to identify a few common factors among those with cardiac complications that, with further research, may help us identify earlier the children with MIS-C who are at greater risk for heart problems.”

The study found that children with cardiac complications had higher levels of natriuretic peptides, which appear in greater numbers when the heart isn’t pumping enough blood to the rest of the body. Additionally, children who developed heart complications also had higher initial white blood cell counts. MIS-C cardiac complications ranged from mild systolic dysfunction to coronary artery abnormalities and/or artery dilation.

This was a retrospective, observational study of 39 patients admitted to Children’s National Hospital from March 2020 to September 2020 who met the Centers for Disease Control and Prevention MIS-C case definition. Patient demographics, clinical features, laboratory values, diagnostic investigations, including echocardiograms, and therapies were extracted from the electronic medical records.

“This syndrome has some similarities to Kawasaki disease, another inflammatory syndrome that is known to cause cardiac complications,” says Dr. Harahsheh. “Thankfully what we’ve learned from studying and treating Kawasaki disease in children has helped us collaborate with partners around the world to find treatments for MIS-C that seem to minimize the impact of these complications, at least in the short term.”

Drs. Packer and van den Acker at the Pediatric Device Innovators Forum

Pediatric Device Innovators Forum explores state of focused ultrasound

For children living with pediatric tumors, less invasive and less painful treatment with no radiation exposure was not always possible. In recent years, the development of technologies like Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) and Low intensity transcranial focused ultrasound (LIFU) is helping to reverse that trend.

This topic was the focus of the recent Pediatric Device Innovators Forum (PDIF) hosted by the National Capital Consortium for Pediatric Device Innovation (NCC-PDI) in partnership with the U.S. Food and Drug Administration’s (FDA) Pediatric Device Consortia (PDC) grant program. A collaboration between Children’s National Hospital and University of Maryland Fischell Institute for Biomedical Devices, NCC-PDI is one of five PDCs funded by the FDA to support pediatric device innovators in bringing more medical devices to market for children.

The discussion, moderated by Kolaleh Eskandanian, Ph.D., MBA, PMP, vice president and chief innovation officer at Children’s National and principal investigator of NCC-PDI, explored the use of focused ultrasound’s noninvasive therapeutic technology for two pediatric indications, Osteoid Osteoma (OO) and Diffuse Intrinsic Pontine Glioma (DIPG), and the ways it can increase the quality of life for pediatric patients while also decreasing the cost of care.

The discussion also examined the most common barriers preventing more widespread implementation of focused ultrasound technology, specifically small sample size for evidence generation, lack of funding opportunities and reimbursement issues that can make or break a technology’s chances at reaching the patients that need it.

Karun Sharma, M.D., director of Interventional Radiology at Children’s National, emphasized the potential for focused ultrasound to treat localized pain relief and treat other diseases that, like OO, do not have any other therapeutic alternative

“At Children’s National, we use MR-HIFU to focus an ultrasound beam into lesions, usually tumors of the bone and soft tissues, to heat and destroy the harmful tissue in that region, eliminating the need for incisions,” says Sharma. “In 2015, Children’s National doctors became the first in the U.S. to use MR-HIFU to treat pediatric osteoid osteoma (OO), a painful, but benign, bone tumor that commonly occurs in children and young adults. The trial demonstrated early success in establishing the safety and feasibility of noninvasive MR-HIFU in children as an alternative to current, more invasive approaches to treat these tumors.”

In November 2020, the FDA approved this MR-HIFU system to treat OO in pediatric patients.

Roger Packer, M.D., senior vice president of the Center for Neuroscience and Behavioral Medicine at Children’s National, also discussed how focused ultrasound, specifically LIFU, has also proven to be an attractive modality for its ability to non-invasively, focally and temporarily disrupt the blood brain barrier (BBB) to allow therapies to reach tumors that, until recently, would have been considered unreachable without severe intervention.

“This presents an opportunity in pediatric care to treat conditions like Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive brain tumor that typically causes death and morbidity,” says Packer.

Packer is planning a clinical trial protocol to investigate the safety and efficacy of LIFU for this pediatric indication.

The forum also featured insight from Jessica Foley, M.D., chief scientific officer, Focused Ultrasound Foundation; Arjun Desai, M.D., chief strategic innovation officer, Insighttec; Arun Menawat, M.D., chairman and CEO, Profound Medical; Francesca Joseph, M.D., Children’s National; Johannes N. van den Anker, M.D., Ph.D., vice chair of Experimental Therapeutics, Children’s National; Gordon Schatz, president, Schatz Reimbursement Strategies; Mary Daymont, vice president of Revenue Cycle and Care Management, Children’s National; and Michael Anderson, MD, MBA, FAAP, FCCM, FAARC, senior advisor to US Department of Health and Human Services (HHS/ASPR) and Children’s National.

Anthony Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care and director of the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Hospital, and Sally Allain, regional head of Johnson & Johnson Innovation, JLABS @ Washington, DC, opened the forum by reinforcing both organizations’ commitment to improving pediatric health.

In September 2020, the Focused Ultrasound Foundation designated Children’s National Hospital as the first global pediatric Center of Excellence for using this technology to help patients with specific types of childhood tumors. As a designated COE, Children’s National has the necessary infrastructure to support the ongoing use of this technology, especially for carrying out future pediatric clinical trials. This infrastructure includes an ethics committee familiar with focused ultrasound, a robust clinical trials research support team, a data review committee for ongoing safety monitoring and annual safety reviews, and a scientific review committee for protocol evaluation.

The Pediatric Device Innovators Forum is a recurring collaborative educational experience designed by the FDA-supported pediatric device consortia to connect and foster synergy among innovators across the technology development ecosystem interested in pediatric medical device development. Each forum is hosted by one of the five consortia. This hybrid event took place at the new Children’s National Research and Innovation Campus, the first-of-its-kind focused on pediatric health care innovation, on the former Walter Reed Army Medical Center campus in Washington, D.C.

To view the latest edition of the forum, visit the NCC-PDI website.

Panelists at the Pediatric Device Innovators Forum

The recent Pediatric Device Innovators Forum (PDIF) exploring the state of focused ultrasound was held at the new Children’s National Research and Innovation Campus, a first-of-its-kind focused on pediatric health care innovation.

3d illustration of blood cells, plasmodium causing malaria disease

International projects spearheaded by Children’s National Neurology leaders

NIH approves grant for clinical trial on pediatric cerebral malaria in Malawi

3d illustration of blood cells, plasmodium causing malaria disease

Cerebral malaria, when patients lapse into coma after developing a malaria infection, is the most severe neurological complication of infection with Plasmodium falciparum.

The National Institutes of Health (NIH) approved a $5.8 million grant for a Phase I/IIa randomized clinical trial of 6-diazo-5-oxo-L-norleucine (DON), a new medication for pediatric cerebral malaria. Douglas Postels, M.D., neurologist at Children’s National Hospital, will serve as the trial’s principal investigator. The clinical trial will enroll participants in Blantyre, Malawi.

More than 400,000 people die each year from malaria. Cerebral malaria, when patients lapse into coma after developing a malaria infection, is the most severe neurological complication of infection with Plasmodium falciparum. Many children who survive are left suffering from neurological complications because of the disease, leaving some unable to walk, see or go to school. Dr. Postels and others are seeking to initiate this clinical trial with the primary goal to save lives and improve the quality of life for children who survive the disease.

“The purpose of this study is to see if DON is safe in the Malawian population,” Dr. Postels said, noting that adult participants will be enrolled in the first year and children subsequently. “Once the medication has proven to be safe, our intention is to expand this research elsewhere in Africa allowing us to enroll more children and evaluate whether DON decreases the likelihood of death or neurological disability in pediatric cerebral malaria.”

DON was originally tested 50 years ago as an anti-cancer agent but was recently repurposed by the National Institute of Allergy and Infectious Diseases (NIAID) for pediatric cerebral malaria. The current clinical trial is a collaborative project with the NIAID scientists who performed the pre-clinical testing with DON.

“There are currently no adjunctive treatments, used in combination with intravenous anti-malarial medications, that decrease death or disability in pediatric cerebral malaria,” Dr. Postels said. “Our hope is that DON will be the “magic bullet” that helps these critically ill children.”

Improving access to epilepsy care in Ethiopia

Over the next three years, Tesfaye Zelleke, M.D., neurophysiologist at Children’s National Hospital, the Comprehensive Pediatric Epilepsy Program team and the Children’s National Global Health Initiative will create a sustainable program to reduce the epilepsy treatment gap in Ethiopia in collaboration with the Ethiopian Ministry of Health.

In a three-tier approach, the program is looking to help children in the country benefit from the increased access to the treatment and care for epilepsy, the most common neurologic disorder affecting about 1% of the population.

Ethiopia is one of the poorest countries in Africa with very limited access to epilepsy care — there are a handful of pediatric neurologists for a population of over 120 million. Only few referral hospitals have neurology clinics and those clinics are largely concentrated in Addis Ababa, the capital city. Improving access to epilepsy care in resource poor countries like Ethiopia would require utilizing non-neurologist providers, a task-shifting model.

“In the first year, we will focus on creating an epilepsy center of excellence, training of trainers (local non-neurologist providers), create treatment guidelines for epilepsy, and produce health education material for families and public,” said Dr. Zelleke. “In the subsequent years, we plan to expand to other areas outside of Addis Ababa — the Ethiopian capital — and collaborate with epilepsy advocacy groups to continue to increase access to care.”

After the three years, Dr. Zelleke and the team have envisioned working closely with the country’s Ministry of Health to further the impact of the project at a national level.

fetus in utero

Loss of placental hormone linked to brain and social behavior changes

fetus in uteroPreterm birth has been shown to increase the risk of autism spectrum disorders and other developmental problems, particularly in males. The more premature a baby is, the greater the risk of either motor or cognitive deficits. What does the preterm baby lose that is so critical to long-term outcomes?

A new pre-clinical study suggests that one factor may be the loss of a placental hormone that the developing brain would normally see in the second half of pregnancy.

The study is the first to provide direct evidence that loss of a placental hormone alters long-term brain development.

In the study, researchers in the laboratory of Anna Penn, M.D., Ph.D., now at Columbia University Vagelos College of Physicians and Surgeons and previously at Children’s National Hospital in Washington, D.C., found that reducing amounts of a single hormone, called allopregnanolone (ALLO), in the placenta caused brain and behavior changes in male offspring that resemble changes seen in some people with autism spectrum disorder.

The study also found that both brain structure and behavioral changes in the subjects could be prevented with a single injection of ALLO in late pregnancy.

“Our study provides new and intriguing insights into how the loss of placental hormones—which happens in preterm birth or if the placenta stops working well during pregnancy—can lead to long-term structural changes in the brain that increase the risk for autism or other neuropsychiatric disorders,” says lead author Claire-Marie Vacher, Ph.D., assistant professor of neonatal sciences in the Department of Pediatrics at Columbia University’s Vagelos College of Physicians and Surgeons. “What’s encouraging is that these disorders may be preventable if diagnosed and treated early.”

The study was published online August 16 in the journal Nature Neuroscience.

The placenta is an organ that provides the fetus with oxygen and nutrients and removes waste products. It also produces hormones, including high levels of ALLO in late pregnancy that may influence brain development. Penn, now the L. Stanley James Associate Professor of Pediatrics at Columbia University Vagelos College of Physicians and Surgeons and chief of neonatology at Columbia and New York-Presbyterian Morgan Stanley Children’s Hospital, coined the term “neuroplacentology” to describe this new field of research connecting placental function to brain development.

About one in 10 infants is born prematurely (and is thus deprived of normal levels of ALLO and other hormones), and many more pregnancies have poor placental function.

For this study, the researchers created a pre-clinical model in which they were able to selectively decrease the production of ALLO during pregnancy so that some developing pups were exposed to sufficient placental ALLO while others were not. Although male and female fetuses were both subjected to ALLO deficiency, only male subjects showed autism-like behaviors after birth. Working with collaborators in Washington, D.C., France, and Canada, the Penn laboratory analyzed brain development and long-term behavioral outcomes in the offspring.

ALLO reduction led to cerebellum changes, autism-like behaviors

The male subjects that lacked placental ALLO had structural changes in the cerebellum, a brain region that coordinates movement and has been linked to autism, while their littermates did not.

“In particular, we observed thickening of the myelin sheaths, the lipid coating that protects nerve fibers and speeds up neural signaling,” Vacher says. The same type of thickening is also known to occur transiently in the cerebellum of some boys with autism.

The degree of myelin thickening in juvenile male subjects correlated with abnormal behavior, the researchers also found. The more the sheath was thickened (as measured by myelin protein levels), the more the male subjects exhibited autism-like behaviors, such as decreased sociability and repetitive activities.

“Our experimental model demonstrates that losing placental ALLO alters cerebellar development, including white matter development. Cerebellar white matter development occurs primarily after birth, so connecting a change in placental function during pregnancy with lingering impacts on later brain development is a particularly striking result,” says Penn.

“The findings provide a new way to understand poor placental function. Subtle but important changes during pregnancy or after delivery may set in motion neurodevelopmental disorders that children experience later in life.”

Similarities with human tissue

To determine if similar changes occur in infants, the researchers also examined post-mortem cerebellar tissues from preterm and full-term infants who had died soon after birth. Analysis of these human tissues showed similar changes in brain proteins when cerebellum from male babies born preterm were compared to male full-term babies.

“This study is an important first step in understanding how placental hormones may contribute to specific human neurobehavioral outcomes. We look forward to continuing our collaboration with Dr. Penn and her team to help define how cerebellar neurons and glia respond to environmental factors, including placental function, that can compromise the developing brain,” says study co-author Vittorio Gallo, Ph.D., interim chief academic officer at Children’s National Hospital and interim director of the Children’s National Research Institute.

Hormone injection reduced autism symptoms

ALLO’s therapeutic potential was then tested in the preclinical model.

Male offspring of the pre-clinical model given a single injection of ALLO in late pregnancy had fewer autism-like behaviors, the researchers found. Similar results were seen after an injection of muscimol, a drug that enhances the function of GABA receptors—the same receptors that respond to ALLO. Myelin protein levels in the developing cerebellum also normalized with the treatment.

“Identifying when key hormone levels are abnormal, and figuring out how and when to adjust these levels, provides an opportunity to intervene,” Penn says. “Performing additional studies with our pre-clinical model, and measuring hormone levels in moms and babies, may lead to earlier treatment to reduce or prevent long-term cognitive and behavioral impairments in high-risk fetuses and newborns.”

A version of this story appeared on the Columbia University newsroom.

The study is titled “Placental endocrine function shapes cerebellar development and social behavior.” The other contributors: Helene Lacaille (Columbia), Jiaqi J. O’Reilly (Columbia), Jacquelyn Salzbank (Columbia), Dana Bakalar (National Institutes of Health, Bethesda, MD), Sonia Sebaoui (Children’s National Hospital, Washington, DC), Philippe Liere (University Paris Saclay, Le Kremlin‐Bicêtre Cedex, France), Cheryl Clarkson-Paredes (George Washington University, Washington, DC), Toru Sasaki (Children’s National Hospital), Aaron Sathyanesan (Children’s National Hospital), Panagiotis Kratimenos (Children’s National Hospital), Jacob Ellegood (Hospital for Sick Children, Toronto, ON), Jason Lerch (Hospital for Sick Children and University of Oxford, John Radcliffe Hospital, Oxford, UK), Yuka Imamura (Pennsylvania State University College of Medicine, PA), Anastas Popratiloff (George Washington University), Kazue Hashimoto-Torii (Children’s National Hospital and George Washington University), and Michael Schumacher (University Paris Saclay).

Yuan Zhu

Yuan Zhu, Ph.D., receives Outstanding Scientist Award

Yuan Zhu

The George Washington University (GW) Cancer Center recently announced the selection of the 2021 GW Cancer Center Awards, recognizing excellence in research, mentorship and early career contributions.

The GW Cancer Center Outstanding Scientist Award was presented to Yuan Zhu, Ph.D., professor of pediatrics at the GW School of Medicine and Health Sciences (SMHS) and Children’s National Hospital. The award is presented to faculty members who make a noteworthy contribution in the areas of basic science, clinical science, translational science or population science.

In his nomination, Dr. Zhu was cited for his contributions to the understanding of the mechanisms underlying the development of tumors and altered brain development arising in the setting of the inherited condition neurofibromatosis type 1 (NF1). “Throughout his career, Dr. Zhu has had a remarkable consistency of focus in his scholarly work, where he has sought to advance new molecular and mechanistic insights to understand the biological basis of NF1 and the cancers arising in individuals affected by this genetic disease.”

You can find a full list of award winners here.

Hands holding letters that spell autism

Gene associated with autism affects social interactions differently in males and females

Hands holding letters that spell autism

The loss function of a gene associated with autism spectrum disorder (ASD), Foxp2, impacts brain circuits that control olfactory processing, social interaction, mating, aggressive and parental behaviors in a pre-clinical model. Sex differences were most notable in females with low social interaction and higher aggression behavior compared to males, suggesting ASD-like behavior in females, according to the study published in Frontiers in Behavioral Neuroscience.

ASD affects social communication and behavior in approximately 1 in 68 people, many of the symptoms appear in the first two years of life, and the disorder is mostly seen in males. Recent studies suggest that FOXP2 mutations have been implicated in a subset of individuals with ASD.

“Our work provides insights into how this gene may function mechanistically to control social interactions in both males and females,” said Joshua Corbin, Ph.D., principal investigator at Children’s National Hospital and senior author. “Foxp2 is an autism susceptibility gene, thus potentially revealing insights into the neurobiological underpinnings of deficits in social communication in neurodevelopmental disorders.”

Dopamine (DA) also plays a role in motivation and reward-seeking behavior. Herrero et al. further found that patterns of Foxp2+ cell activation in the amygdala, a structure involved in social motivation, differed in females and males in response to DA, with greater activation in females. Although how this ties together with the function of Foxp2 in social behavior remains to be elucidated, this finding suggests an intriguing link between this important neuropeptide and Foxp2 function.

FOXP2 mutations in humans are associated with disorders affecting speech and language. The scientific community has extensively studied the Foxp2 gene in other brain regions, most notably those involved in language production, such as the cerebral cortex and basal ganglia (striatum). Still, little is known regarding the function of Foxp2 in male or female social behavior, which has a large amygdala component.

“Rational interventions for human disorders and diseases relies on an understanding of the underlying biology of these conditions,” said Corbin. “Our work presents an important step toward elucidating the genetic pathways required for neurotypical social behavior.”

To better understand the role that Foxp2 plays in the amygdala-linked social behaviors, the researchers used a comprehensive panel of behavioral tests in male and female subjects. The research team relied on visual observation and video recordings to collect and score the behavioral data, work that was conducted as part of Children’s National NIH funded DC-IDDRC.

The set of behavioral tests included a “social interaction assay” that utilized a 3-chamber device, an “olfactory habituation and discrimination assay,” which pooled several odors with a cotton swab and a “maternal aggression assay” that measured aggressive encounters of a lactating female to a male intruder.

The researchers also compared the ex vivo tissue samples of female and male subjects to assess protein changes in the amygdala that might affect the activation of DA pathways.

blood glucose monitoring system

Patterns of continuous glucose monitoring use in young children after T1D diagnosis

blood glucose monitoring system

The findings suggest that, when clinically appropriate, continuous glucose monitoring initiation near or at the time of diagnosis benefits glycemic outcomes in young children when followed by sustained use.

Continuous glucose monitoring (CGM) is a blood glucose monitoring device worn on the body that is linked to positive glycemic outcomes in people with Type 1 diabetes (T1D). However, very little research has examined CGM use and glycemic outcomes in young children, particularly those newly diagnosed with T1D.

A new Diabetes Technology and Therapeutics study led by Randi Streisand, Ph.D., C.D.C.E.S., Chief of Psychology and Behavioral Health at Children’s National Hospital, and others identified four meaningful trajectories of CGM use among young children across 18-months post-T1D diagnosis: those who “always” used CGM; those who got on CGM later but stayed on it (“late/stable”); those who used CGM inconsistently; and those who “never” used CGM. The investigators conducted a study of 157 parents of young children (1-6 years) newly diagnosed with T1D who enrolled in a behavioral intervention.

Importantly, the authors found that those with private insurance were more likely than those with only public insurance to be in the “always” and “late/stable” groups (as opposed to the “never” group). Those in the “always” and “late/stable” groups also had better glycemic outcomes than those in the “never group” at 18-months post-T1D diagnosis.

“This research highlights that insurance type can be a barrier to accessing CGM,” Dr. Streisand noted. “Further, this is one of the first studies, among newly diagnosed young children, to show that CGM initiation at diagnosis or near diagnosis followed by sustained use is associated with better glycemic outcomes compared to never initiating CGM, supporting findings from other studies conducted with older youth.”

The findings inform clinical care with patients as it suggests that, when clinically appropriate, CGM initiation near or at the time of diagnosis benefits glycemic outcomes in young children when followed by sustained use. This is the only study to examine patterns of CGM use among 1-6-year-old children newly diagnosed with T1D over the first 18-months post-diagnosis.

“It was exciting to find differences in glycemic outcomes based on CGM initiation and use in this unique population,” Dr. Streisand said. However, the authors concluded that, given the health benefits of CGM, further exploration of barriers to CGM access and use among some families is needed.

In addition to Dr. Streisand, other Children’s National co-authors include Brynn Marks, M.D., M.S. HPEd.; Carrie Tully, Ph.D.Maureen Monaghan, Ph.D., C.D.E. , and Christine Wang, Ph.D.

Miriam Bornhorst

Miriam Bornhorst, M.D., receives DOD New Investigator Award

Miriam Bornhorst

Miriam Bornhorst, M.D., clinical director of the Gilbert Neurofibromatosis Institute at Children’s National Hospital, received the Department of Defense’s Neurofibromatosis Research Program New Investigator Award.

This award, which is funded by the U.S. Department of Defense, has granted $450,000 in funds which Dr. Bornhorst hopes to use towards a study for patients with Neurofibromatosis Type 1 (NF1).

“There is very little known about metabolism in NF1, but we know that abnormalities in metabolism can not only affect a person’s overall health, but may also influence how tumors develop and grow,” Dr. Bornhorst explained.

Patients with NF1 can have defining clinical features related to growth and energy metabolism, such as short stature, low weight and decreased bone mineral density, findings that are more prominent in patients with high plexiform neurofibroma (a nerve sheath tumor) burden. The mechanism for this metabolic phenotype and its association with plexiform neurofibromas is not currently understood.

Preliminary data and the work of others suggest that the MAPK pathway may play a role in metabolism and Mek-inhibitor (MEKi) treatment, which decreases activity of the MAPK pathway and promotes weight gain in patients with NF1. Dr. Bornhorst’s study will be the first to explore global metabolism in NF1, determine which metabolic pathways are most active in plexiform neurofibromas and define how metabolomic signatures change during MEKi treatment.

“These findings will improve management and may lead to novel treatment options for patients with NF1,” she said. “It is my hope that the grant funding received for my study will not only allow me to generate data that will answer questions about metabolism in NF1, but foster interest in this topic so there are more opportunities for researchers in the future.”

The NFRP was initiated in 1996 to provide support for research of exceptional scientific merit that promotes the understanding, diagnosis, and treatment of neurofibromatosis (NF) including NF type 1 (NF1) and type 2 (NF2) and schwannomatosis. Since it was first offered, 346 new Investigator Award applications have been received and only 79 have been recommended for funding – with Children’s National receiving one in the latest grant cycle. The Gilbert Family Neurofibromatosis Institute at Children’s National is one of the world’s largest programs and the longest standing program in the United States.

Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.