Selected Grantee Publications
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- 15 results found
- Alzheimer's Disease
- Somatic Cell Genome Editing
- Microscopy
Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype
Gross et al., Nature Communications. 2025.
https://www.nature.com/articles/s41467-025-57632-w
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease in which immune cells infiltrate the central nervous system and promote deterioration of myelin and neurodegeneration. The capacity to regenerate myelin in the central nervous system diminishes with age. In this study, researchers used 2- to 3-month-old (young), 12-month-old (middle-aged), and 18- to 22-month-old (aged) C57BL/6 male and female mice. Results showed an upregulation of the senescence marker P16ink4a (P16) in microglial and macrophage cells within demyelinated lesions. Notably, treatment of senescent cells using genetic and pharmacological senolytic methods leads to enhanced remyelination in young and middle-aged mice but fails to improve remyelination in aged mice. These results suggest that therapeutic targeting of senescence-associated secretory phenotype components may improve remyelination in aging and MS. Supported by ORIP (R24OD036199), NIA, NINDS, and NIMH.
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.
Suppressing APOE4-Induced Neural Pathologies by Targeting the VHL-HIF Axis
Jiang et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39874294
The ε4 variant of human apolipoprotein E (APOE4) is a major genetic risk factor for Alzheimer’s disease and increases mortality and neurodegeneration. Using Caenorhabditis elegans and male APOE-expressing mice, researchers determined that the Von Hippel-Lindau 1 (VHL-1) protein is a key modulator of APOE4-induced neural pathologies. This study demonstrated protective effects of the VHL-1 protein; the loss of this protein reduced APOE4-associated neuronal and behavioral damage by stabilizing hypoxia-inducible factor 1 (HIF-1), a transcription factor that protects against cellular stress and injury. Genetic VHL-1 inhibition also mitigated cerebral vascular injury and synaptic damage in APOE4-expressing mice. These findings suggest that targeting the VHL–HIF axis in nonproliferative tissues could reduce APOE4-driven mortality and neurodegeneration. Supported by ORIP (R24OD010943, R21OD032463, P40OD010440), NHGRI, NIA, and NIGMS.
Liver-Specific Transgenic Expression of Human NTCP In Rhesus Macaques Confers HBV Susceptibility on Primary Hepatocytes
Rust et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937851
This study establishes the first transgenic nonhuman primate model for hepatitis B virus (HBV). Male and female rhesus macaques were engineered to express the human HBV receptor, NTCP (hNTCP), specifically in the liver. Researchers used PiggyBac transposon technology to introduce a liver-specific NTCP transgene into embryos, which were then implanted into surrogate females. The resulting offspring expressed hNTCP in hepatocytes and demonstrated high susceptibility to HBV infection. This model overcomes the species-specific limitations of HBV research, providing a powerful tool for studying HBV biology and evaluating HBV treatments in a clinically relevant model system. Supported by ORIP (P51OD011092), NIDA, and NIAID.
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.
A Comprehensive Atlas of AAV Tropism in the Mouse
Walkey et al., Molecular Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39863928
Over the past three decades, adeno-associated viruses (AAVs) have emerged as the leading viral vector for in vivo gene therapy. This study presents a comprehensive atlas of AAV tropism in male and female mice, evaluating 10 naturally occurring AAV serotypes across 22 tissues using systemic delivery. Researchers employed a fluorescent protein activation approach to visualize AAV transduction patterns and detected transduction of unexpected tissues, including in adrenal glands, testes, and ovaries. Biodistribution closely matched the fluorescent signal intensity. This publicly available data set provides valuable insights into AAV vector targeting and supports optimal serotype selection for basic research and preclinical gene therapy applications in murine models. Supported by ORIP (U42OD026645, U42OD035581, U42OD026635), NCI, NHLBI, NICHD, and NIDDK.
In Vivo Expansion of Gene-Targeted Hepatocytes Through Transient Inhibition of an Essential Gene
De Giorgi et al., Science Translational Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937884
This study explores Repair Drive, a platform technology that selectively expands homology-directed repair for treating liver diseases in male and female mice. Through transient conditioning of the liver by knocking down an essential gene—fumarylacetoacetate hydrolase—and delivering an untraceable version of that essential gene with a therapeutic transgene, Repair Drive significantly increases the percentage of gene-targeted hepatocytes (liver cells) up to 25% without inducing toxicity or tumorigenesis after a 1-year follow-up. This also resulted in a fivefold increase in expression of human factor IX, a therapeutic transgene. Repair Drive offers a promising platform for precise, safe, and durable correction of liver-related genetic disorders and may expand the applicability of somatic cell genome editing in a broad range of liver diseases in humans. Supported by ORIP (U42OD035581, U42OD026645), NCI, NHLBI, and NIDDK.
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.
Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Stat3 Mediates Fyn Kinase-Driven Dopaminergic Neurodegeneration and Microglia Activation
Siddiqui et al., Disease Models & Mechanisms. 2024.
https://pubmed.ncbi.nlm.nih.gov/39641161
The FYN gene is a risk locus for Alzheimer’s disease and several other neurodegenerative disorders. FYN encodes Fyn kinase, and previous studies have shown that Fyn signaling in dopaminergic neurons and microglia plays a role during neurodegeneration. This study investigated Fyn signaling using zebrafish that express a constitutively active Fyn Y531F mutant in neural cells. Activated neural Fyn signaling in the mutant animals resulted in dopaminergic neuron loss and induced inflammatory cytokine expression when compared with controls. Transcriptomic and chemical inhibition analyses revealed that Fyn-driven changes were dependent on the Stat3 and NF-κB signaling pathways, which work synergistically to activate neuronal inflammation and degeneration. This study provides insight into the mechanisms underlying neurodegeneration, identifying Stat3 as a novel effector of Fyn signaling and a potential translational target. Supported by ORIP (R24OD020166).