Selected Grantee Publications
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- 81 results found
- Pediatrics
- Stem Cells/Regenerative Medicine
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.
Biocompatibility and Bone Regeneration by Shape Memory Polymer Scaffolds
Gasson et al., Journal of Biomedical Materials Research Part A. 2025.
https://pubmed.ncbi.nlm.nih.gov/39404147
This study evaluates the potential of shape memory polymer (SMP) scaffolds for bone tissue engineering, focusing on their biocompatibility and ability to support bone regeneration. Researchers first demonstrated biocompatibility of SMP scaffolds in 12-week-old male Wistar rats and confirmed cell adhesion, proliferation, and differentiation, while promoting bone regeneration in 6 month-old male New Zealand white rabbits with induced bone defects. These scaffolds combine mechanical strength with the capacity to enhance biological healing, making them a promising tool for orthopedic applications. These findings highlight the potential of SMPs as a versatile platform for tissue engineering applications, combining structural support with biocompatibility to enhance bone repair and healing outcomes. Supported by ORIP (T32OD011083).
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.
Lipid Nanoparticle-Mediated mRNA Delivery to CD34+ Cells in Rhesus Monkeys
Kim et al., Nature Biotechnology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578569
Blood cells, which are derived from hematopoietic stem cells (HSCs), promote pathologies including anemia, sickle cell disease, immunodeficiency, and metabolic disorders when dysfunctional. Because of the morbidity that results from the bone marrow mobilization and chemotherapy patient conditioning of current HSC therapies, novel treatment strategies that deliver RNA to HSCs are needed. Researchers found a lipid nanoparticle (LNP), LNP67, that delivers messenger RNA (mRNA) to murine HSCs in vivo and human HSCs ex vivo without the use of a cKit-targeting ligand. When tested in 7- to 8-month-old male and female rhesus monkeys, LNP67 successfully delivered mRNA to CD34+ cells and liver cells without adverse effects. These results show the potential translational relevance of an in vivo LNP–mRNA drug. Supported by ORIP (U42OD027094, P51OD011107), NIDDK, and NCATS.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
Immune Perturbation Following SHIV Infection Is Greater in Newborn Macaques Than in Infants
Shapiro et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39190496
This study investigates immune perturbation following simian-human immunodeficiency virus (SHIV) infection in newborn and infant male and female rhesus macaques, highlighting significant differences in pathogenesis. Although plasma viremia and lymph node viral DNA were similar, newborns exhibited higher viral DNA levels in gut and lymphoid tissues 6–10 weeks postinfection than infants. Additionally, newborns showed greater immune alterations, with skewed monocyte and CD8+ T-cell profiles and minimal type I interferon responses. These findings suggest age-dependent immunological responses to SHIV and underscore the vulnerability of newborns to HIV-related pathogenesis, providing insights into immune development and pediatric HIV management. Supported by ORIP (P51OD011092, U42OD023038, U42OD010426) and NIAID.
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
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.
Enterohemorrhagic Escherichia coli (EHEC) Disrupts Intestinal Barrier Integrity in Translational Canine Stem Cell-Derived Monolayers
Nagao et al., Microbiology Spectrum. 2024.
https://pubmed.ncbi.nlm.nih.gov/39162490/
EHEC produces Shiga toxin, which causes acute colitis with symptoms such as hemolytic uremic syndrome and bloody diarrhea. The researchers developed a colonoid-derived monolayer model to understand EHEC’s impact on canine gut health. Colonoid-derived monolayers co-cultured with EHEC demonstrated key differences compared with the control and nonpathogenic E. coli co-cultures. Scanning electron microscopy displayed EHEC aggregated and attached to the microvilli. EHEC-infected monolayers demonstrated significantly weakened membrane integrity and increased inflammatory cytokine production, specifically TNFα. The researchers developed a novel in vitro model that offers an additional platform for understanding the mechanisms of EHEC pathogenicity, developing therapeutics for EHEC, and studying additional enteric pathogens. Supported by ORIP (K01OD030515, R21OD031903).
Human Stem Cell-Derived Cardiomyocytes Integrate Into the Heart of Monkeys With Right Ventricular Pressure Overload
Scholz et al., Cell Transplantation. 2024.
https://journals.sagepub.com/doi/10.1177/09636897241290367
Patients with single-ventricle congenital heart defects suffer from right ventricular pressure overload (RVPO). Researchers developed a novel pulmonary artery banding (PAB) rhesus macaque model to induce RVPO. This study investigated the efficacy of human induced pluripotent stem cell cardiac lineage cell (hiPSC-CL) delivery at low or high dose into adult male and female rhesus macaques with right ventricular dysfunction. The findings indicate that hiPSC-CLs were successfully grafted and integrated to match the surrounding host right ventricle myocardium. These results suggest hiPSC-CL therapy is a potential adjunctive treatment for RVPO, but future research will be needed to elucidate the beneficial effects. Supported by ORIP (P51OD011106).