Selected Grantee Publications
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- 66 results found
- nci
- Vaccines/Therapeutics
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.
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.
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.
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.
Engineered Deletions of HIV Replicate Conditionally to Reduce Disease in Nonhuman Primates
Pitchai et al., Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39116226/
Current antiretroviral therapy (ART) for HIV is limited by the necessity for continuous administration. Discontinuation of ART leads to viral rebound. A therapeutic interfering particle (TIP) was developed as a novel single-administration HIV therapy using defective interfering particles. TIP treatment in two humanized mouse models demonstrated a significant reduction in HIV viral load. TIP intervention was completed 24 hours prior to a highly pathogenic simian immunodeficiency virus (SIV) challenge in a nonhuman primate (NHP) rhesus macaque infant model. Compared to untreated SIV infection, NHPs that received TIP treatment displayed no visible signs of SIV-induced AIDS and exhibited improved seroconversion and a significant survival advantage to the 30-week clinical endpoint. Peripheral blood mononuclear cells isolated from HIV-infected patients showed that TIP treatment reduced HIV outgrowth. This study demonstrates the potential use of a single-administration TIP for HIV treatment. Supported by ORIP (P51OD011092, U42OD010426), NCI, NIAID, and NIDA.
Administration of Anti-HIV-1 Broadly Neutralizing Monoclonal Antibodies With Increased Affinity to Fcγ Receptors During Acute SHIV AD8-EO Infection
Dias et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-51848-y
Anti-HIV broadly neutralizing antibodies (bNAbs) mediate virus neutralization and antiviral effector functions through Fab and Fc domains, respectively. This study investigated the efficacy of wild-type (WT) bNAbs and modified bNAbs with enhanced affinity for Fcγ receptors (S239D/I332E/A330L [DEL]) after acute simian-HIVAD8-EO (SHIVAD8-EO) infection in male and female rhesus macaques. The emergence of the virus in the plasma and lymph nodes occurred earlier in macaques given DEL bNAbs than in those given WT bNAbs. Overall, the administration of DEL bNAbs revealed higher levels of immune responses. The results suggest that bNAbs with an enhanced Fcγ receptor affinity offer a potential therapeutic strategy by targeting HIV more effectively during early infection stages. Supported by ORIP (P40OD028116), NCI, and NIAID.
Dual Blockade of IL-10 and PD-1 Leads to Control of SIV Viral Rebound Following Analytical Treatment Interruption
Pereira Ribeiro et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39266691
Pereira Ribeiro et al. tested a hypothesis that blockading two immune molecules, IL-10 and PD‑1, following treatment interruption could help control viral rebound in antiretroviral therapy (ART)–treated rhesus macaques infected with simian immunodeficiency virus (SIV), a nonhuman analogue of HIV. When measured at 24 weeks following treatment interruption, durable control of viral rebound was seen in 9 of 10 combo-treated macaques. The investigators also found that they could predict the control of viral rebound based on the induction of inflammatory cytokines, proliferation of effector CD8+ T cells, and reduced expression of BCL-2 in CD4+ T cells prior to treatment interruption. These results could provide a way to achieve long-lasting control of HIV infection after discontinuing ART. Supported by ORIP (U42OD011023, P51OD011132), NCI, and NIAID.