Selected Grantee Publications
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- 84 results found
- Vaccines/Therapeutics
- Genetics
Small-Diameter Artery Grafts Engineered from Pluripotent Stem Cells Maintain 100% Patency in an Allogeneic Rhesus Macaque Model
Zhang et al., Cell Reports Medicine. 2025.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00075-8
Globally, the leading cause of death is occlusive arterial disease, but surgical revascularization improves patient prognosis and reduces mortality. Vascular grafts often are needed in coronary bypass surgery for surgical revascularization. However, the clinically approved option for small-diameter revascularization is autologous vascular grafts, which require invasive harvesting methods, and many patients lack suitable vessels. Researchers developed a novel method for graft development using arterial endothelial cells (AECs), derived from pluripotent stem cells (PSCs), on expanded polytetrafluoroethylene using specific adhesion molecules. This study used a 6- to 13-year-old male rhesus macaque arterial interposition grafting model. The major histocompatibility complex mismatched wild-type (MHC-WT) AEC grafts were successful when implanted in rhesus macaques and attracted host cells to the engraftment, leading to 100% patency for 6 months. The results highlight a novel strategy for generating artery grafts from PSC-derived MHC-WT AECs that overcomes current challenges in graft development and may have future clinical applications. Supported by ORIP (P51OD011106, S10OD023526), NCI, and NHLBI.
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.
Systematic Ocular Phenotyping of 8,707 Knockout Mouse Lines Identifies Genes Associated With Abnormal Corneal Phenotypes
Vo et al., BMC Genomics. 2025.
https://pubmed.ncbi.nlm.nih.gov/39833678
Corneal dysmorphologies (CDs) are a group of acquired but predominantly genetically inherited eye disorders that cause progressive vision loss and can be associated with systemic abnormalities. This study aimed to identify candidate CD genes in humans by looking at knockout mice with targeted deletions of orthologous genes that exhibited statistically significant corneal abnormalities. Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes; 176 (83%) genes have not been implicated previously in CD. Bioinformatic analyses implicated candidate genes in several signaling pathways (e.g., integrin signaling pathway, cytoskeletal regulation by Rho GTPase, FAS signaling pathway), which are potential therapeutic targets. Supported by ORIP (U42OD011175, R03OD032622, UM1OD023221), NEI, and NHGRI.
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.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
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.
Targeting Pancreatic Cancer Cell Stemness by Blocking Fibronectin-Binding Integrins on Cancer-Associated Fibroblasts
Wu et al., Cancer Research Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/39785683
Cancer-associated fibroblasts (CAFs) stimulate the formation and progression of pancreatic adenocarcinoma (PDAC) through the generation of extracellular matrix (ECM). Researchers developed a bispecific antibody (bsAb) that targets α5β1 and αvβ3 integrins expressed on CAFs. Blockade using the bsAb resulted in reduced assembly of fibronectin and collagen fibers in vitro. An antifibrotic effect was observed when CAFs were plated for 72 hours prior to bsAb treatment; pre-deposited ECM was disrupted. Six- to 8-week-old female nu/nu mice treated with bsAb demonstrated fewer tumors and reduced tumor stiffness compared with those exposed to only CAFs co-injected with PDAC cells. These results support a potential novel PDAC therapeutic that targets CAF-mediated fibronectin assembly and ECM production. Supported by ORIP (K01OD030513) and NCI.
Integrative Multi-omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes in Ovarian Cancer
Rosario et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39638782
Recurrent ovarian cancer (OC) is the deadliest gynecological malignancy, with a 5-year survival rate of 50% and a median progression-free survival (PFS) of 1.9 to 2.1 months. A trial cohort of 40 patients was treated with a combination of the anti-PD-1 pembrolizumab, the anti–vascular endothelial growth factor bevacizumab, and cyclophosphamide. The investigators conducted a multi-omics analysis—including transcriptomic analysis, digital spatial profiling, 16s-rRNA sequencing, and metabolomics—to understand the underlying mechanisms for the enhanced PFS to a median of 10.2 months and overall response rate of 47.5%. Multi-omics analysis highlighted the formation of tertiary lymphoid structures known to improve responses to immunotherapy, differential microbial patterns, and alterations in the metabolites in three key metabolism pathways that enhanced immune response in patients to produce a durable clinical response. These findings highlight the importance of the tumor microenvironment and the gut microbiome, along with its metabolites, in elevating the efficacy of the cocktail therapy in recurrent OC patients, thereby enhancing their survival and quality of life. Supported by ORIP (S10OD024973) and NCI.