Selected Grantee Publications
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- 7 results found
- HIV/AIDS
- Pediatrics
- CRISPR
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).
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.
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.
Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome
Lloyd, Mammalian Genome. 2024.
https://pubmed.ncbi.nlm.nih.gov/39254744
The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.
Preclinical Safety and Biodistribution of CRISPR Targeting SIV in Non-Human Primates
Burdo et al., Gene Therapy. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11090835/
Nonhuman primates have served as a valuable resource for evaluating novel eradication and cure strategies for HIV infection. Using a male rhesus macaque model, researchers demonstrated the safety and utility of CRISPR gene-editing technology for targeting integrated simian immunodeficiency virus (SIV). Their work suggests that a single intravenous inoculation for HIV gene editing can be utilized to reach viral reservoirs throughout the body. Additionally, no off-target effects or abnormal pathology were observed. Together, these findings support the continued development of HIV eradicative cure strategies using CRISPR technology in humans. Supported by ORIP (P40OD012217, U42OD021458).
Thresholds for Post-Rebound SHIV Control after CCR5 Gene-Edited Autologous Hematopoietic Cell Transplantation
Cardozo-Ojeda et al., eLife. 2021.
https://elifesciences.org/articles/57646
Investigators developed a mathematical model to project the minimum threshold of C-C chemokine receptor type 5 (CCR5) gene-edited cells necessary for a functional cure from HIV. This was based on blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted hematopoietic stem and progenitor cells (HSPCs) are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76–94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur. Supported by ORIP (P51OD010425), NCATS and NIAID.