Mass General Brigham for Children Research
Overview
The research mission of the Department of Pediatrics is to advance translational basic, clinical and population science related to the health and development of infants, children, and adolescents. Research at MGfC recognizes the challenges and opportunities for child health research dictated by the changing social, economic and health care policy landscape in the US, including the shift toward Precision Medicine. Across the Department, our research integrates multidisciplinary clinical and scientific expertise with local, regional, national and international collaborations.
With the appreciation that biological, social and environmental events beginning during gestation and continuing into childhood can strongly influence disease onset during childhood and beyond, we are expanding our integrated models focused on pre-clinical/early and translational clinical studies to provide the rationale for possible therapeutic and/or preventive interventions. Our overarching goal is to improve the lives of children and families through science. A current strategic priority is to develop new effective personalized and preventive strategies for disorders starting in infancy and childhood by integrating multi-level, multisystem data ranging from the molecular to the whole child analyzed and modeled through Artificial Intelligence technology in order to prevent or reverse development of disease. To better coordinate our effort and to integrate our scientific mission within the MGH Research Institute we have established the Pediatric Translational Research Center (PTRC) in which basic, translational, clinical, and community-based research are blended to deliver state-of-the-art clinical care, to provide superb training opportunities, and foster cutting-edge discoveries to achieve our mission. Furthermore, during the entire COVID-19 pandemic we supported the MGB effort to develop diagnostic and therapeutic tools to face this unprecedented scientific and clinical challenge. To support this effort, we established a Pediatric Biobank that has collected biospecimens from more than 2500 children exposed or affected by SARS-CoV2 infection, including 75 children with Multiorgan Inflammatory Syndrome (MIS-C). Now our focus is on the many more children affected by Long COVID.
Research focus areas
Adolescent Medicine
The overall mission of the division of Adolescent Medicine is to elevate the health and well-being of adolescents and young adults throughout Boston, New England, and the US through cutting-edge clinical care, research, medical education, and advocacy. The Focus of the division is providing primary and subspecialty care for adolescents and young adults across a range of conditions, including eating disorders, menstrual disorders, contraceptive counseling, sexually transmitted infections, pelvic pain, weight management, mental health, and substance use. Historically the division provides high-quality care in primary care and subspecialty services, and eliminates disparities by race, ethnicity, language, and gender. The division also works to build a world-class adolescent health research program with federal, foundation, and philanthropic funding. Under the leadership of its Chief, Dr. Scott Haddland, the division focuses on developing leading adolescent medical education for medical students, residents, and ultimately, adolescent medicine fellows and draws on clinical, research, and educational expertise to advocate for youth across the US.
Allergy & Immunology
The research mission for Pediatric Allergy & Immunology is to partner with our patients to advance new therapeutic, preventative and educational interventions for the millions of children affected by the spectrum of allergic disease including both IgE- and non IgE-mediated forms of food allergy and asthma. A major research focus within the Division is on the mechanisms of immune-mediated food hypersensitivities including IgE-mediated food allergy, chronic gastrointestinal inflammatory diseases related to food allergy such as eosinophilic esophagitis and allergic proctocolitis. To advance this research effort, The Food Allergy Center at Massachusetts General Hospital (FAC@MGH) was established in 2010 as a multi-disciplinary research and clinical care center with the core participation of clinicians and investigators from Allergy / Immunology (from the Departments of both Pediatrics and Medicine), as well as Gastroenterology, Psychology, Nutrition, Pathology, and the Harvard Catalyst-supported, MGH Translational and Clinical Research Center (TCRC). At the time of its inception, there were no clinical trials, interventional or otherwise, focused on food allergy at MGH. To date, the FAC@MGH has initiated than more than 50 IRB-approved studies on food allergy. These studies represent almost 3,000 research participants in total, more than 2,000 of whom have undergone oral food provocation tests (food challenges). These include randomized interventional trials for food allergy, including two studies funded by NIAID – (NCT01750879, NCT02698033), enrolling 100s of patients and conducting 1000s of study visits, demonstrating the capacity to carry out randomized interventional trials for the food allergic population, including the necessary regulatory compliance (cGCP and ICH), pediatric and adult patient recruitment, data management and all other necessary requirements.
The Gastrointestinal Microbiome and Allergic Proctocolitis (GMAP) and NIAID-funded Systems Biology of Early Atopy (SUNBEAM) studies have demonstrated our capacity to also carry out larger population cohort / low risk interventional trials: GMAP is an observational healthy newborn cohort study that enrolled 1000 consecutive newborns from a single multi-provider general pediatrics over site over a three year period beginning May 1, 2014. The study aims to identify risk factors for the development of both IgE and non-IgE presentations of food allergy and collects infant stool (at <1 week, 2 weeks, 1, 2, 4, 6, 9, 12, 18, 24 months) and blood (at 1, 2 and 3 years of age) and some other biospecimens (e.g., maternal breast milk). There have now been six primary research papers now published from this cohort addressing not only risk factors of both food protein-induced allergic proctocolitis – often the earliest manifestation of immune-mediated adverse reactivity to dietary antigen – and IgE food allergy, but evaluating other aspects of infant health in this cohort including growth, dysbiosis, and acid-suppressing medications. The SUNBEAM study, funded as part of the FAC’s role in the Consortium for Food Allergy Research (CoFAR), seeks to identify root causes from the environment, diet, hereditary factors and the body’s immune system to be able to better predict, prevent, and treat these allergic conditions. Still enrolling, the cohort is recruiting 2250 infants and their parents from across 10 sites in the US.
Immune phenotyping in the setting of interventional trials of patients with peanut allergy have revealed significant insights made by the laboratories of Drs. Shreffler and Patil. Dr. Shreffler’s group is pursuing studies of antigen-specific T cells, finding that the expansion of pathogenic effector memory T cells, which are suppressed during oral immunotherapy, is associated with allergen sensitivity at baseline, independently of IgE. Poor response to OIT is also associated with
To complement the therapeutic discovery efforts, Dr. Michael Pistiner leads our program on Prevention, Education and Advocacy. This program is one of the largest in the country targeting high risk infants by collaborating with primary care pediatricians in the MGH/Partners network to lower the barriers of access to expand the early childhood diet to include common allergens – the most effective means of allergy prevention currently proven – and to develop a national model for doing this in other settings. Because of Dr. Pistiner’s efforts, effective Dec 2018, we have also become the second site for an NIAID-funded prevention study, led by our colleagues at Johns Hopkins Univiersity and have attracted other new extramural funding for education and prevention as well. Dr. Pistiner has brought in >300K of new funding for this program.
In 2016, the FAC@MGH was awarded a seven-year UM1 award by NIAID to be part of the Consortium for Food Allergy Research (CoFAR), the first time for any center in New England and only one of six in the US. In 2019 we were awarded additional funding (UM2) for this project. The Division enjoys strong collaborations with academic and industry groups at BWH (The Channing Laboratory), BCH, MIT, The Broad Institute, Vedanta Biosciences, Infinant Health, and others.
Cardiology
The Pediatric/Congenital Cardiology division is involved in research in basic science and health services research to understand the causes of congenital heart disease and to study clinical interventions to improve the provision of pediatric cardiovascular care and foster a patient centered environment. We are fortunate to have a robust clinical and academic environment to promote these research endeavors. Members of our service are engaged in basic science research understanding the genetic etiologies of vascular pathology such as aortopathies (for example, Marfan syndrome and Loeys Dietz syndrome). We are also involved in health services research specifically in the area of patient safety and quality as it pertains to pediatric cardiology. We have ongoing investigations evaluating diagnostic accuracy of cardiac imaging, investigations evaluating of parental health literacy among congenital heart disease families, and studies of resource use among patients undergoing congenital heart surgery. Our preventative cardiology service has collaborated with the Harvard T.H. Chan School of Public Health on projects to examine outpatient and wireless means to track physical activity and caloric intake. This year we published on means to distinguish MISC from other inflammatory disorders in children.
Critical Care Medicine
A major focus of the division of Pediatric Critical Care Medicine is preventing, treating and understanding mechanisms of acute brain injury. Our neurocritical care research efforts include basic science and translational studies to understand cellular and molecular events that occur following different forms of acute brain injury, with the goal of finding new therapies that mitigate specific maladaptive responses and improve outcomes using mouse models that we hope will translate to humans. Dr. Whalen’s lab uses genetic mouse models, cell and molecular biological techniques and experimental as well as FDA approved drugs to understand mechanisms driving disease in experimental models of adolescent concussion, adult cerebral contusion and intracerebral hemorrhage. In addition, we seek to inform public health trauma prevention strategies to reduce pediatric traumatic brain injury through our Trauma and Injury Prevention Outreach Project (TIPOP). This multidisciplinary group focuses research, community outreach, and education on the most common causes of pediatric injuries leading to emergency department visits and PICU admissions, including motor vehicle accidents, window falls, firearms violence, ingestions, burns and recreational-related trauma. Our division is also dedicated to better understanding the long-term neurological sequelae of critical illness to better inform our practice, particularly as it relates to long-term exposure to pain and sedation medications. Lastly, in collaboration with the Anesthesiology Center for Critical Care Research (ACCCR), we continue to contribute to innovative and impactful work demonstrating safety and efficacy of high-dose nitric oxide (NO) in the treatment of pneumonia and ARDS.
Endocrinology
The focus of research in the Division of Pediatric Endocrinology is to enhance the understanding of endocrine systems and endocrine disease during the childhood, adolescent and transition years. Areas of particular interest include investigations into bone health in Type 1 diabetes (Dr. Deborah Mitchell), the role of exercise in ameliorating comorbidities associated with obesity, including polycystic ovary syndrome (Dr. Rachel Whooten), genetic determinants of pubertal timing (Dr. Kemal Topaloglu), impact of perinatal glycemia and GLP-1 receptor agonist use during pregnancy on infant and child outcomes (Dr. Jacqueline Maya), and endocrine determinants of metabolic-dysfunction associated steatotic liver disease and type 2 diabetes (Dr. Takara Stanley). We also encourage discrete, clinically focused projects that foster an environment of inquiry and investigation among our faculty and fellows. In order to optimize funding opportunities and maintain a strong research base within the division, we actively engage in intra- and extra-mural collaborations with other laboratories to create a rich and interactive reinforcing environment that will lead to changes in medical care paradigms for children with endocrine disorders. Currently the Pediatric Endocrine faculty include two researchers with R01 funding, one with U01 funding, one with K23 funding, and one with an ADA Career Development Grant.
Pediatric Gastroenterology, Hepatology and Nutrition
Mucosal Immunology and Biology Research Center
Our mission is to expand clinical, basic and translational research in pediatric gastroenterology and nutrition to provide better outcomes for pediatric patients. Using a multidisciplinary approach, our major basic research mission is to characterize the role of the enteric mucosa and its mucosal barrier function at the interface between microbial luminal stimuli and lymphoid effector responses. We focus on the enterocyte and its involvement in microbial “crosstalk,” lymphoid-nerve-epithelial interactions and inappropriate developmental responses secondary to epigenetic pressure by the gut microbiota during the first 1000 days of life. We also look at host-pathogen interactions during infection as well as how the enterocyte functions both as a barrier to antigen trafficking and as a site for the beneficial effects of probiotics in chronic inflammation. Finally, we are interested in the gut-brain axis, particularly in regard to the interaction of small intestinal and blood brain barriers in the context of neuroinflammatory diseases. Our researchers examine strategies used by gut microbiota to affect the host and how these interactions lead to both local and systemic chronic inflammation and autoimmunity in the Mucosal Immunology and Biology Research Center (MIBRC).
In the effort to bring the best idea to clinical fruition, researchers at the MIBRC active clinical and translational research to implement personalized and primary preventive medicine is carried out in our Airway, Voice and Swallowing Center for Children; the Center for Celiac Research and Treatment; the Center for Diagnostic, Therapeutic and Interventional Endoscopy; the Center for Inflammatory Bowel Disease; the Center for Nutrition; the Center for Pediatric Hepatobiliary and Pancreatic Disease; the Food Allergy Program; the Liver Transplantation Program; the Lurie Center for Autism Pediatric Gastroenterology Program; the Neurogastroenterology Program and the Pediatric Weight Center.
Fasano Lab
Hurley Lab
Mou Lab
Digestive Disease Summer Research Program
GEMMA
Pediatric Aerodigestive Center Research
General Academic Pediatrics
Our internationally-known academic research division is dedicated to improving the health of children and adolescents through research on prevention and reduction of the burden of chronic disease among children; reduction and elimination of disparities in children’s health and healthcare; evaluating the costs and cost-effectiveness of interventions and screening guidelines; and improving the health of populations across the lifecourse through innovations in research, patient care, education, and community advocacy. As part of this work we address key pediatric health issues such as obesity, autism, smoking, addiction, childhood chronic conditions, food access, mental health of children and their families, and stress. We also conduct research to prepare and support primary care pediatricians in the delivery of health care innovations, leveraging clinical and community partnerships to implement and sustain effective interventions.
Division faculty have a wide variety of research specialties, including:
- Improving the care for families impacted by substance use disorder
- Childhood obesity prevention and treatment
- Cost effectiveness of HIV screening and treatment
- Access to health food
- Strategies to address tobacco use and exposure in families
- Maternal-child health throughout the life course
- Childhood chronic conditions
- Parent and sibling resiliency interventions
- Fatherhood
- Early Intervention
Genetics and Metabolism
The Division of Medical Genetics and Metabolism at MGfC is at the forefront of advancing healthcare, providing diagnostic services alongside innovative translational research. We specialize in developmental, congenital, and metabolic disorders, offering lifelong care and guidance for patients. Our work spans from foundational cellular and molecular research to impactful clinical and translational studies, combining genetic counseling, diagnostics, and proactive management to enhance health outcomes and address diseases effectively. Our specialized clinics cater to a wide range of conditions, including Metabolic disorders, Lysosomal Storage Diseases, Mitochondrial diseases, Turner Syndrome, Williams Syndrome, 22q Deletion Syndrome, Stickler Syndrome, Klinefelter Syndrome, Hereditary Hemorrhagic Telangiectasia, and Pediatric Cancer Predisposition, showcasing our comprehensive care approach. These programs all have associated research efforts. Our Metabolism Program offers diagnosis and care for metabolic diseases affecting both children and adults, supporting individuals throughout their lives. Our Down Syndrome Clinic sets a gold standard in both patient care and research, actively participating in pioneering clinical trials aimed at improving cognitive function in individuals with Down syndrome, novel modalities for improving sleep apnea, and improving access to care. We have also earned international recognition for our expertise in Williams Syndrome and Pitt Hopkins Syndrome, with global referrals seeking our specialized knowledge. In addition, we are deeply involved in clinical trials for lysosomal storage and mitochondrial diseases, pioneering genetic advancements and enhancing our understanding of these complex conditions. We have been instrumental in implementing cutting-edge genetic technologies throughout the MGB system via our involvement in several committees and partnerships with fellow genetics specialists. Our division also serves as one of the clinical sites for the NIH-sponsored Undiagnosed Diseases Network (UDN), evaluating patients who have remained undiagnosed despite the use of advanced clinical techniques, including whole exome sequencing. We have a 37% success rate in reaching diagnoses for these patients. The UDN team at MGH has been pivotal in identifying 16 new genetic disorders and expanding the phenotypic spectrum of 8 known disorders. We have established a Rare and Undiagnosed Diseases Program at MGB, supported by philanthropy. This program includes a comprehensive repository of biological samples, genomic data, and patient phenotype information, enrolling over 1,000 patients. This resource has been a catalyst for numerous research projects, including the in vitro functional validation of genetic variants of uncertain significance, which has led to the identification of several novel disease-causing mutations. Our commitment to advancing genetics is reflected in our collaboration with providers and departments across the hospital and researchers around the world, highlighting the significant role genetics plays in shaping medical practice.
Global Health
Founded in 2010, the Division of Global Health at the MassGeneral for Children is engaged in interdisciplinary research, education and clinical care aimed at improving the wellbeing of the most vulnerable children in our global community. The division includes faculty, fellows and staff with diverse experiences and interests but a shared dedication to enhancing the health and development of children across the globe. Building upon MassGeneral Hospital for Children’s long-standing commitment to scientific and clinical innovation, our faculty and staff work to improve medical education, combat prematurity, birth asphyxia, neonatal sepsis, childhood pneumonia, diarrheal illness, antibiotic resistance, and the health impacts of HIV at several sites across the globe.
Hematology/Oncology
The physician scientists and clinicians in the Division of Pediatric Hematology-Oncology have been active in both basic science and translational/clinical research in both cancer and benign hematologic diseases. In collaboration with our pediatric subspecialty colleagues, we have multi-disciplinary programs and clinics for children with CNS tumors, long-term survivors of childhood cancer, stroke, and hemophilia/bleeding disorders. We are active members and investigators in several different cooperative oncology groups(Childrens Oncology Group, Pacific Neuro-oncology Consortium, and St. Jude Research Hospital) and participate in therapeutic and non-therapeutic clinical trials. . In the area of benign hematology, we have had significant growth in our pediatric stroke and Hemophilia/bleeding disorder programs. These multi-disciplinary clinics provide comprehensive care and engage patients in clinical research projects. We have ongoing lab based and translational research projects in our Division and with our MGH colleagues in Pathology, Radiology, Internal Medicine, and Neurosurgery. One of these projects in collaboration with Dr. Bryan Choi from neuro-oncology involves the development of a CAR T-cell protocol for children with relapsed ependymomas. We have also collaborated with Dr. Michael Gee from radiology to evaluate PET-MRI in comparison to PET-CT for staging children with solid tumors. Another exciting study with Dr. Shannon Stott involves peripheral blood assays to identify and quantitate cell free DNA and exosomes from children with medulloblastoma and Ewing;s sarcoma. The goal of this non-invasive technology is to monitor tumor response and progression as an adjunct to imaging. Our brain team team has been participating in molecular based clinical trials and studying the long term outcomes of Proton Beam RT for children with medulloblastoma and other brain tumors. Long term follow-up of our childhood cancer survivors has been an integral component of our program for tracking late effects of therapy and providing appropriate subspecialty care.
Dr. Verena Göbel, a physician-scientist in our program, has been a leading investigator studying lumenogenesis and cell polarity. These studies have important implications for tumor invasion and metastasis. Dr. David Sweetser, a physician scientist in both hem-onc and genetics, has a new project involving the interaction of the bone marrow microenvironment and leukemia stem cells. The tumor microenvironment is an important area of investigation in cancer pathogenesis. We have had a very productive collaboration with Dr. Miguel Rivera in Pathology whose lab is focused on elucidating the molecular pathogenesis of medulloblastoma and Ewing’s sarcoma. Dr. Miguel Rivera’s research has been studying the genetic and epigenetic drivers in Ewing sarcoma and medulloblastoma. Learn more about our Pediatric Radiation Oncology Clinical Research
Infectious Disease
The Pediatric Infectious Disease Unit has been active in both basic science and in translational/clinical research. Dr. Chadi El Saleeby has participated in an extensive series of studies relating to methicillin-resistant staphylococcal infection in hospitalized children. Dr. Lakshmi Ganapathi has been studying the care of adolescents using injectiable drugs at integrated care centers in several locations in India where HIV and drug use are managed in a coordinated manner. She has also studied the use of SARS-COV 2 monoclonal antibodies in children. Dr. Jason Harris’s externally funded cholera research efforts encompass investigation of the immune response to Vibrio cholerae infection with an emphasis on vaccine response and development, and exploration of the molecular epidemiology and ecology of V. cholerae. He has also initiated a series of studies relating to the serologic response to SARS-CoV 2 infection and demonstrated disparities in SARS-CoV 2 prevalence in relation to racial, ethnic, and other social determinants. In addition, Dr. Harris has turned to the problem of antibiotic resistance in pediatric infections and has published a provocative report demonstrating the surprisingly high rate of gram negative bacteremia due to multiply resistant isolates among children hospitalized with pneumonia. Dr. Azza Idris has been investigating the role of novel antimalarial monoclonal antibodies in studies that include studies of monoclonal binding mechanisms and in clinical trials of human controlled infection. Dr. Vandana Madhavan has reported on clinical features of SARS-CoV 2 associated Multisystem Inflammatory Syndrome of Children (MIS-C). Dr. Ann Murray has been participating in a multicenter study of undergraduate medical education. Dr. Shaw Warren’s pivotal discovery over the past several years of the differential genomic responses between humans and mice to sepsis and inflammation and led to the establishment of a large multicenter project to investigate mechanisms responsible for species-specific sensitivity to inflammation. The consortium has completed its investigations and is nearing the completion of manuscripts reporting their findings. Dr. Mark Pasternack has been part of a clinical and research consortium focused on the study of children with PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection).
Lurie Center for Autism
At the Lurie Center for Autism our primary mission is to enhance the lives of individuals and families affected by autism spectrum disorder (ASD) and other neurodevelopmental conditions. We do this through exceptional clinical care and comprehensive, multi-faceted research. Importantly, the patient population that the Lurie Center serves is over 50% adults, and our research activities reflect this demographic with research studies aimed at understanding and improving care across the lifespan. Research at the Lurie Center aims to answer critical questions on the biological mechanisms of ASD and related disorders, develop methods for assessing symptom changes with treatment, and advance strategies to enhance patient care for individuals with ASD of all ages.
The Lurie Center is committed to a collaborative approach to research and aims to connect our research programs to other scientific nodes within the greater Boston area and beyond. For this reason, we launched the Lurie Center Faculty Associate Program two years ago, which has since grown to include 16 Faculty Associates. These research faculty, at MGB and other leading institutions across the country, are key members of the Lurie Center’s scientific community. Faculty Associates participate in meetings, lead and collaborate on research projects, and apply their specific expertise to advancing autism research. MGB faculty interested in becoming a Lurie Center Faculty Associate are invited to reach out.
In tandem to growing and nurturing this network, we are expanding resources to support our growing collaborative network. This year, we launched the Lurie Center Research Registry, an IRB-approved platform where interested individuals, primarily Lurie Center patients and their family members, can express not only their willingness to participate in research but also specify the types of studies most relevant to them. This tool allows us to better match potential research participants with suitable studies, enhancing participant experience and streamlining recruitment for investigators.
Likewise, to facilitate access to patient samples, we initiated a biobanking effort in April 2023. At that time, among the over 100,000 individuals in the MGB Biobank, only about 100 were identified as autistic. Partnering with the MGB Biobank, we are working to increase the representation of autistic individuals within this repository, which stores DNA, serum, plasma, and health survey data. This initiative aims to support research on ASD and accelerate discoveries in the field. This year, we achieved the milestone of enrolling our 100th participant in the Biobank. We plan to continue to grow this resource in 2025 and expand into banking peripheral blood mononuclear cells (PBMCs).
With regard to specific collaborations, one notable partnership underway is a collaboration with Dr. Gagan Joshi of the Alan and Lorraine Bressler Program for Autism Spectrum Disorder and Dr. Elise Robinson of MGH’s Center for Genomic Medicine as well as the Broad Institute of MIT and Harvard. Together, we are facilitating access to genetic testing for individuals with ASD through the SPARK (Simons Foundation Powering Autism Research for Knowledge) study. Led by Dr. Wendy Chung (now at Boston Children’s Hospital), SPARK was launched in 2016 to create a large, long-term research cohort. The cohort now has over 275,000 participants, including 100,000 individuals with ASD and 175,000 of their family members. We are pleased to be partnering with the Spark team to stand up an MGB site for this study and thereby contribute to a comprehensive and accessible dataset that is already enabling large-scale studies of ASD while returning genetic findings to families.
Through these and other means, we aim to expand our impact on the autism research community including patients and families who are waiting for answers.
Lurie Center Summer Student Research Fellowship
Neonatology and Newborn Medicine
The research effort in the Division of Newborn Medicine is multifaceted and ranges from developmental lung biology to quality improvement to psychology. All research projects share a common mission: to advance scientific knowledge aimed at improving the care and treatment of our very vulnerable patients and their families. Our research portfolio is reflective of the broad clinical spectrum of issues in our patient population – from extremely low gestational age neonates and the myriad medical issues they face, to full-term infants with various congenital anomalies and those born with physiologic dependence to opioids due to in-utero exposure. Our basic research focuses on the identification of molecular pathways that link prematurity, genetic factors, and in-utero and early life exposure to the health of our patients in infancy and beyond. We have built patient-specific stem cell and animal models of early childhood diseases to identify these molecular pathways as therapeutic targets. Our translational research focuses, in large part, on neuroprotection strategies, including an examination of those factors that affect neurodevelopmental outcomes following perinatal neurological insults and in-utero substance exposure. More recently we have complimented this work with studies on the health inequities and the psychologic resilience (and vulnerability) of our patients and their caregivers.
MGBfc Division of Newborn Medicine Summer Student Research Program
Ai Lab
Nephrology
Research activity in pediatric nephrology is focused on defining genetic defects leading to kidney disease, with or without changes in mineral ion homeostasis, and to thereby gain basic insights into biology. These efforts will improve diagnosis, management, and clinical outcome. Our group thus continues to contribute to the molecular definition of monogenic forms of nephrotic and nephritic renal diseases, and other inherited disorders involving the kidney, including the identification of LRP2 variants contributing to glomerular loss of early progressive kidney disease and the role of coenzyme Q10 in steroid-resistant nephrotic syndrome. We furthermore helped assessing kidney function in patients with spinal muscular atrophy and sickle cell disease, and in collaboration with colleagues at the NIH, our group contributed to the evaluation of mineral ion and bone abnormalities in patients with nephropathic cystinosis.
Besides these efforts, we have a major focus on the discovery of molecular defects that cause rare genetic disorders affecting the regulation of mineral ion homeostasis. Of particular interest is the identification of genetic mutations leading to different forms of pseudohypoparathyroidism (PHP) and hypoparathyroidism (HP). In addition to our previous contributions, we recently identified a novel deletion within the GNAS locus without leading to loss-of-methylation at one of the differentially methylated regions within GNAS. We furthermore showed that patients with PHP1B due to a STX16 deletion do not develop PTH-resistance before the age of two years. Thus, screening children of affected and unaffected female carriers of STX16 deletion, need to be followed through laboratory testing thus allowing early treatment, if indicated, and consequently avoiding potentially severe sequelae from hypocalcemia and/or hyperphosphatemia, including basal ganglia calcifications. Most recently, a novel retrotransposon insertion leading to autosomal dominant PHP1B was discovered through long-read DNA sequencing, which had escaped detection through conventional whole genome sequencing. This 2.8-kb insertion contains a polyadenylation signal, which could imply that an mRNA involved in establishing methylation at exon A/B undergoes polyadenylation prematurely, which can now be explored further once cell lines from an affected patient from this family are available.
Another retrotransposon was recently identified in a PHP1B patient, who was initially thought to be affected by the sporadic variant of PHP1B. However, her methylation abnormalities at the GNAS locus were unusual in that she showed a loss-of-methylation at the maternal DMRs, but only an incomplete gain-of-methylation at exon NESP. Eventually, we determined that the retrotransposon is located centromeric of antisense (AS) exon 1, on the maternal GNAS allele. The same insertion was found in her younger brother, who was found to be also affected by PHP1B, and that both children had inherited the mutation from their mother, who had inherited it from her father. Both retrotransposons comprise tandem polyadenylation signals that probably terminate a nascent RNA derived from the NESP exon that is required for establishing or maintain methylation at exon A/B. Besides these advances related to inherited forms of PHP1B, a mouse model of the human disease with loss-of-methylation restricted to the exon 1A DMR has now been developed. Renewal of the RO1 grant related to PHP1B was submitted in early November; funding, if approved, should start in the summer of 2025.
We had developed a “humanized” mouse in which the endogenous PTH/PTHrP receptor (PTHR1) is replaced with the cDNA encoding the human PTH1R. This engineered mouse has no obvious phenotype thus allowing, through iGONAD, the introduction of mutations that are responsible for Jansen’s disease. “Humanized” mice with the H223R mutation show major growth plate abnormalities and some laboratory abnormalities typically observed in the human disease, but most of these animals die by two months of age. In contrast, mice with the T410R mutation are viable and allowed the generation of a stable colony with the disease. These animals also show profound growth plate abnormalities, increased levels of ionized calcium with reduced phosphate and PTH levels. Injection of an inverse PTH agonist leads in these mice to a decline in ionized calcium levels, along with an increase in PTH, thus providing proof-of-principle that an inverse agonist can potentially be used for the treatment of Jansen disease. The growth plate abnormalities in the T410R mice are similar to those in the R485X mouse, a model of Eiken disease, at least in the newborn period, namely a much-delayed differentiation of proliferating chondrocytes into hypertrophic cells. Funding of the RO1 grant renewal was started in the summer of 2024.
These studies will continue to provide further pre-clinical data for the development, through the NIH-TRND program, of PTH-IA for the treatment of patients affected by Jansen’s disease. GMP-grade PTH-IA was produced through the NIH and toxicology studies and provided no evidence for obvious side effects in short- and long-term studies in rats. An IND application was submitted with the investigators from the NIH to the FDA, which was approved in late October 2023. NIH-IRB approval is pending, but it likely that the first clinical trials in adult patients affected by Jansen’s disease will be started in the next few months.
Pediatric Palliative Care
The mission of the MGfC Pediatric Palliative Care Service is to enhance quality of life and ease physical, spiritual, and emotional suffering for patients with serious or life limiting illnesses and their families. With our interdisciplinary approach we support and advocate for informed decision making through exploration of a patient and families’ wishes and goals. We collaborate with a child’s primary and specialist teams to tailor communication and foster understanding of medical information that patients and caregivers receive. We apply evidenced based strategies in the relief of pain and other symptoms. Our team prioritizes a holistic and compassionate approach to honoring a child’s personhood as they navigate their illness within the context of their family, culture, and community.
Our division hosts the Pediatric Palliative Care Innovation and Discovery Lab co lead by Drs. Joanne Wolfe and Veronica Dussel. The lab is comprised of interprofessional investigators collectively aiming to improve the well-being of seriously ill pediatric patients and their families. Investigators focus on identifying and measuring developmentally appropriate outcomes for patients and their families and then systematically develop and rigorously evaluate interventions aimed at improving these outcomes. They seek to impact care throughout the illness trajectory from diagnosis, advanced illness, transitions to adulthood, end-of-life, and bereavement, and across all ages, from perinatal to young adult. Key interventions currently under development and evaluation include understanding and mitigating symptom distress in seriously ill children, goals of care and decision-making support for parents, adolescents, and young adults, and the impact of subspecialty palliative care interventions in children with cancer and other serious illnesses.
Pulmonary
The Pulmonary Division upholds an extensive research focus, with significant attention on COVID-19. Under the leadership of Drs. Lael Yonker, the team is dedicated to the study of MIS-C and long-haul COVID. Drs. Peter Moschovis is engaged in analyzing the physiological outcomes of long-haul COVID. In a second area of inquiry, Dr. Yonker explores airway inflammation in cystic fibrosis (CF). The third research area, guided by Drs. Kinane and Eichler, targets gene therapy for Canavan's disease, using AAV vectors to transport the ASPA gene to the impacted neurons. The fourth research area, led by Drs. Kinane, Hartnick, and Gipson, is the use of hypoglossal nerve stimulators to treat obstructive sleep apnea. In the educational research arena, Dr. Ben Nelson has implemented a CPC-like program, contributing case studies to Pediatric Pulmonology. Another research initiative, led by Dr. Kinane, focuses on integrating AI in medical student education, with projects that utilize AI for grading and feedback, and for developing personalized clerkships through Deep learning techniques.
Rheumatology
Investigators in the Pediatric Rheumatology Program lead and participate in clinical research that include observational research studies, as well as investigator-initiated outcomes and adverse event studies, across a wide range of childhood-onset rheumatic diseases. As part of such research efforts, our faculty members are continuing enrollment of patients as a member site of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, which is a long-term, multi-site prospective observational study focused on safety and disease outcomes that combines FDA Phase IV post-marketing surveillance with outcomes research.
Other research in our program has focused on creating and improving guidelines for the safety monitoring of children receiving rituximab and strategies for preventing immunosuppression-related infections among high-risk patients with pediatric-onset rheumatologic diseases (Dr. Rothman and Dr. Natter), short- and long-term outcomes from the PCORI-funded CARRA Registry STOP-JIA clinical trial (the largest pragmatic treatment trial of patients with polyarticular JIA to date) (Dr. Natter), expert reviews article regarding usage of the EHR for enhancing care in pediatric rheumatology (Dr. Natter), and ongoing research collaborations with colleagues in Oral Maxillofacial Surgery at MGH and elsewhere regarding evidence-based, multidisciplinary assessment and treatment of JIA-associated temporo-mandibular joint arthritis that have resulted in multiple peer-reviewed publications (Dr. Rothermel and Dr. Natter).