Selected Grantee Publications
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- 13 results found
- Pediatrics
- 2025
- 2021
Structures of Respiratory Syncytial Virus G Bound to Broadly Reactive Antibodies Provide Insights into Vaccine Design
Juarez et al., Scientific Reports. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11906780
Respiratory syncytial virus (RSV) is one of the leading causes of severe lower respiratory infection in both infants and older adults. RSV viral entry and modulation of the host immunity is mediated by attachment glycoprotein RSV G binding to the chemokine receptor CX3CR1. Antibodies isolated from RSV-exposed individuals have shown great promise in host protection. Researchers using an ORIP-funded electron microscope, in conjunction with X-ray crystallography, have solved the structure of these antibodies bound to the RSV G protein and identified a novel dual antibody binding region. The presence of dual antibody binding sites indicates the potential to elicit antibody responses that resist virus escape. These findings will help develop next-generation RSV prophylactics and provide insight for new concepts in vaccine design. Supported by ORIP (S10OD027012, S10OD025097), NIAID, NHGRI, and NIGMS.
De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome
Booth et al., Brain. 2025.
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf035/8004980?login=true
DDX39B is a core component of the TRanscription-EXport (TREX) super protein complex. Recent studies have highlighted the important role of TREX subunits in neurodevelopmental disorders. Researchers describe a cohort of six individuals (male and female) from five families with disease-causing de novo missense variants or inherited splice-altering variants in DDX39B. Three individuals in the cohort are affected by mild to severe developmental delay, hypotonia, history of epilepsy or seizure, short stature, skeletal abnormalities, variable dysmorphic features, and microcephaly. Using a combination of patient genomic and transcriptomic data, in silico modeling, in vitro assays, and in vivo Drosophila and zebrafish models, this study implicates disruption of DDX39B in a novel neurodevelopmental disorder called TREX-complex-related neurodevelopmental syndrome. Supported by ORIP (U54OD030165).
Early Results of an Infant Model of Orthotopic Cardiac Xenotransplantation
Mitchell et al., Journal of Heart and Lung Transplantation. 2025.
https://pubmed.ncbi.nlm.nih.gov/39778609
This study evaluated the potential of genetically engineered pig hearts for human pediatric heart failure patients, with 11 infantile pig heart transplants performed in size-matched infant baboons (Papio anubis) (sex not specified). All grafts supported normal cardiac functions post-operatively, and six animals survived beyond 3 months. While early cardiac function was not a limiting factor for survival, systemic inflammation led to pulmonary edema and pleural effusions, which impeded long-term outcomes. These findings highlight the feasibility of cardiac xenotransplantation in infants and underscore the need for targeted therapies to manage inflammation and improve survival. Supported by ORIP (P40OD024628) and NHLBI.
Dysregulation of mTOR Signalling Is a Converging Mechanism in Lissencephaly
Zhang et al., Nature. 2025.
https://pubmed.ncbi.nlm.nih.gov/39743596
Lissencephaly (smooth brain) is a rare genetic condition, with such symptoms as epilepsy and intellectual disability and a median life expectancy of 10 years. This study reveals that reduced activity of the mTOR pathway may be a common cause of lissencephaly. Researchers used laboratory-grown brain models (organoids) and sequencing and spectrometry techniques to identify decreased mTOR activation in two types of lissencephaly disorders: p53-induced death domain protein 1 and Miller–Dieker lissencephaly syndrome. Pharmacological activation of mTOR signaling with a brain-selective mTORC1 activator molecule, NV-5138, prevented and reversed the morphological and functional defects in organoids. These findings suggest that mTOR dysregulation contributes to the development of lissencephaly spectrum disorders and highlight a potential druggable pathway for therapy. Supported by ORIP (S10OD018034, S10OD019967, S10OD030363), NCATS, NHGRI, NICHD, NIDA, NIGMS, NIMH, and NINDS.
Preclinical Use of a Clinically-Relevant scAAV9/SUMF1 Vector for the Treatment of Multiple Sulfatase Deficiency
Presa et al., Communications Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/39870870
This study evaluates a gene therapy strategy using an adeno-associated virus (AAV)/SUMF1 vector to treat multiple sulfatase deficiency (MSD), a rare and fatal lysosomal storage disorder caused by mutations in the SUMF1 gene. Researchers delivered the functional gene to male and female Sumf1 knockout mice either neonatally or after symptom onset. Neonatal treatment via cerebral spinal fluid extended survival up to 1 year, alleviated MSD symptoms, and restored normal behavior and cardiac and visual function without toxicity. Treated tissues showed widespread SUMF1 expression and enzymatic activity. These findings support the translational potential of this gene replacement therapy for clinical use in MSD patients. Supported by ORIP (U42OD010921, U54OD020351, U54OD030187) and NCI.
Single-Cell Transcriptomics Predict Novel Potential Regulators of Acute Epithelial Restitution in the Ischemia-Injured Intestine
Rose et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39853303
Following ischemia in the small intestine, early barrier restoration relies on epithelial restitution to reseal the physical barrier and prevent sepsis. Pigs share a similar gastrointestinal anatomy, physiology, and microbiota with humans. Researchers used neonatal and juvenile, 2- to 6-week-old male and female Yorkshire cross pigs to determine upstream regulators of restitution. Single-cell sequencing of ischemia-injured epithelial cells demonstrated two sub-phenotypes of absorptive enterocytes, with one subset presenting a restitution phenotype. Colony-stimulating factor-1 (CSF1) was the only predicted upstream regulator expressed in juvenile jejunum compared with neonatal jejunum. An in vitro scratch wound assay using IPEC-J2 cells showed that BLZ945, a colony-stimulating factor 1 receptor antagonist, inhibited restitution. Ex vivo ischemia-injured neonatal pig jejunum treated with exogenous CSF1 displayed increased barrier function. This study could inform future research focused on developing novel therapeutics for intestinal barrier injury in patients. Supported by ORIP (T32OD011130, K01OD028207), NCATS, NICHD, and NIDDK.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
Dynamics and Origin of Rebound Viremia in SHIV-Infected Infant Macaques Following Interruption of Long-Term ART
Obregon-Perko et al., JCI Insight. 2021.
https://pubmed.ncbi.nlm.nih.gov/34699383/
Animal models that recapitulate human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics, mechanisms of disease, and testing of vaccines and therapeutics. A group of male pigtail macaques (PTMs) were euthanized either 6- or 21-days after SARS-CoV-2 viral challenge and demonstrated mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, virus-targeting T cells were predominantly CD4+, increases in circulating inflammatory and coagulation markers, pulmonary pathologic lesions, and the development of neutralizing antibodies were observed. Collectively, the data suggests PTMs are a valuable model to study COVID-19 pathogenesis and may be useful for testing vaccines and therapeutics. Supported by ORIP (P51OD011104) and NIAID.
A Novel Non-Human Primate Model of Pelizaeus-Merzbacher Disease
Sherman et al., Neurobiology of Disease. 2021.
https://www.sciencedirect.com/science/article/pii/S096999612100214X
Pelizaeus-Merzbacher disease (PMD) in humans is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Investigators report on three spontaneous cases of male neonatal rhesus macaques (RMs) with clinical symptoms of hypomyelinating disease. Genetic analysis revealed that the parents of these related RMs carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These RMs represent the first reported NHP model of PMD, providing an opportunity for studies to promote myelination in pediatric hypomyelinating diseases, as other animal models for PMD do not fully mimic the human disorder. Supported by ORIP (R24OD021324, P51OD011092, and S10OD025002) and NINDS.
Protection of Newborn Macaques by Plant-Derived HIV Broadly Neutralizing Antibodies: A Model for Passive Immunotherapy During Breastfeeding
Rosenberg et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00268-21
Preventing vertical transmission of HIV to newborns is an unmet medical need in resource poor countries. Using a breastfeeding macaque model with multiple simian-human immunodeficiency virus challenge, researchers assessed the protective efficacy of two human broadly neutralizing antibodies (bnAbs) against HIV, PGT121 and VRC07-523, which are produced by a plant expression system. Despite the transient presence of plasma viral RNA, the bnAbs prevented productive infection in all newborns with no sustained plasma viremia, compared to viral loads ranging from 103 to 5x108 in four untreated controls. Thus, plant-expressed antibodies show promise as passive immunoprophylaxis in a breastfeeding model in newborns. Supported by ORIP (U42OD023038, P51OD011092) and NIAID.