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- Pediatrics
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.
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.
Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Reinecke et al., Clinical Cancer Research. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11739783/
The leading cause of deaths in the pediatric osteosarcoma is due to lung metastasis. A current clinical need is the development of therapies that disrupt the later stages of metastasis. Researchers used 6- to 8-week-old female C57BL/6 and CB17-SCID mice to understand how tumor cells disrupt the lung microenvironment to promote tumor growth. Single-cell RNA sequencing and spatial transcriptomics demonstrated osteosarcoma–epithelial cell interactions in a chronic state of wound healing in the lung. Nintedanib administration significantly disrupted metastatic progression compared with the vehicle control, demonstrating a potential novel therapeutic for combating osteosarcoma lung metastasis. Supported by ORIP (K01OD031811), NCI, and NCATS.
Bone Marrow Transplantation Increases Sulfatase Activity in Somatic Tissues in a Multiple Sulfatase Deficiency Mouse Model
Presa et al., Communications Medicine. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11502872/pdf/43856_2024_Article_648.pdf
Multiple Sulfatase Deficiency (MSD) is a rare genetic disorder where patients demonstrate loss of function mutations in the SUMF1 gene, resulting in a severe reduction in sulfatase activity. This enzyme deficiency causes impaired lysosomal function and widespread inflammation, leading to clinical manifestations like neurodegeneration, vision and hearing loss, and cardiac disease. The researchers evaluated the therapeutic potential of hematopoietic stem cell transplant (HSCT) to initiate cross-correction, where functional sulfatase enzymes secreted from the healthy donor cells are taken up to restore function in enzyme-deficient host cells. Bone marrow from healthy male and female B6-Sumf1(+/+) mice were transplanted into B6-Sumf1(S153P/S153P) mice, a model for MSD. The results showed that HSCT is suitable to rescue sulfatase activity in peripheral organs, such as the liver, spleen, and heart, but is not beneficial alone in inhibiting the central nervous system pathology of MSD. Supported by ORIP (U54OD020351, U54OD030187, U42OD010921) and NCI.
Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Nelson et al., Science Immunology. 2024.
https://www.science.org/doi/10.1126/sciimmunol.adm7097
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env—SOSIP—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut. Supported by ORIP (P51OD011107), NCI, and NIAID.
A Defect in Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism and Causes Elevated Ceramide Levels
Dutta et al., Nature Metabolism. 2023.
https://pubmed.ncbi.nlm.nih.gov/37653044/
Human mitochondrial enoyl coenzyme A reductase (Mecr), required for the last step of mitochondrial fatty acid synthesis (mtFAS), is linked to pediatric-onset neurodegeneration, but with unknown mechanisms. Researchers investigated phenotypes of mecr mutants in Drosophila and human-derived fibroblasts. They found that loss of function of Mecr in the whole body resulted in a defect in Fe-S cluster biogenesis and increased iron levels, leading to elevated ceramide levels and lethality in flies. Similar elevated ceramide levels and impaired iron homeostasis were observed human-derived fibroblasts with Mecr deficiency. Neuronal loss of Mecr led to progressive neurodegeneration in flies. This study pointed out a mechanistic link between mtFAS and neurodegeneration through Mecr. Supported by ORIP (R24OD022005, R24OD031447), NICHD, and NINDS.
Infection of the Maternal–Fetal Interface and Vertical Transmission Following Low-Dose Inoculation of Pregnant Rhesus Macaques (Macaca mulatta) with an African-Lineage Zika Virus
Koenig et al., PLOS ONE. 2023.
https://doi.org/10.1371/journal.pone.0284964
Researchers examined transmission of Zika virus to nonhuman primate fetuses during pregnancy. Even with a low dosage of inoculation of the dams, the investigators found that the Zika virus infected fetuses, despite the presence of a “placental fortress,” which normally protects fetuses during gestation. This transmission illustrates the high level of infectivity threat that Zika poses, which may increase if mosquitoes expand their global habitats. Understanding how Zika breaches the placental barrier will help researchers develop strategies to prevent fetal infection during pregnancy and thereby prevent adverse outcomes, such as brain malformation defects. Supported by ORIP (P51OD011106, S10OD023526), NIAID, NCI, and NIGMS.
Infant Rhesus Macaques Immunized Against SARS-CoV-2 Are Protected Against Heterologous Virus Challenge 1 Year Later
Milligan et al., Science Translational Medicine. 2023.
https://doi.org/10.1126/scitranslmed.add6383
The Moderna and Pfizer–BioNTech mRNA vaccines received emergency use authorization for infants 6 months and older in June 2022, but questions remain regarding the durability of vaccine efficacy against emerging variants in this age group. Using a two-dose vaccine regimen consisting of stabilized prefusion Washington-strain spike protein encoded by mRNA and encapsulated in lipid nanoparticles, the investigators immunized 2-month-old rhesus macaques of both sexes. They found that the immune responses persisted and protected from severe disease after heterologous challenge with the Delta variant 1 year later. The decay kinetics of vaccine-induced neutralizing antibody responses in the infant monkeys are comparable to those observed in adult humans and nonhuman primates. Supported by ORIP (P51OD011107), NIAID, and NCI.
De Novo Variants in EMC1 Lead to Neurodevelopmental Delay and Cerebellar Degeneration and Affect Glial Function in Drosophila
Chung et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac053
Variants in EMC1, which encodes a subunit of the endoplasmic reticulum (ER)–membrane protein complex (EMC), are associated with developmental delay in children. Functional consequences of these variants are poorly understood. The investigators identified de novo variants in EMC1 in three children affected by global developmental delay, hypotonia, seizures, visual impairment, and cerebellar atrophy. They demonstrated in Drosophila that these variants are loss-of-function alleles and lead to lethality when expressed in glia but not in neurons. This work suggests the causality of EMC variants in disease. Supported by ORIP (R24OD022005, R24OD031447), NINDS, and NICHD.