Selected Grantee Publications
- Clear All
- 29 results found
- Nonhuman Primate Models
- CRISPR
- Microscopy
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.
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.
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.
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.
Indoleamine-2,3-Dioxygenase Inhibition Improves Immunity and Is Safe for Concurrent Use with cART During Mtb/SIV Coinfection
Singh et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39114981/
HIV and tuberculosis (TB) coinfection can lead to TB reactivation that is caused by chronic immune system activation. Researchers explored indoleamine-2,3-dioxygenase (IDO) inhibition as a host-directed therapy (HDT) to mitigate immune suppression and TB reactivation in a rhesus macaque Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) model. The IDO inhibitor D-1-methyl tryptophan improved T-cell immunity, reduced tissue damage, and controlled TB-related inflammation without interfering with the efficacy of combinatorial antiretroviral therapy (cART). These findings support IDO inhibition as a potential HDT in HIV/TB coinfection, providing a strategy to balance immune control while preventing TB reactivation in cART-treated patients. Supported by ORIP (S10OD028732, U42OD010442, S10OD028653) and NIAID.
Three Novel Neoplasms in Nancy Ma's Owl Monkeys (Aotus nancymaae)
Bacon et al., Veterinary Pathology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39692093/
Researchers have identified three previously unreported tumor types in male and female Nancy Ma’s owl monkeys (Aotus nancymaae), a nonhuman primate species that is rarely associated with tumors. Although past cases in owl monkeys were mostly linked to Herpesvirus saimiri–induced lymphoma, this research expands the understanding of tumor development in this species. These findings highlight potential new disease patterns and could inform veterinary care and biomedical research involving owl monkeys. Continued monitoring and investigation of tumors in New World primates are crucial for ensuring animal welfare and research integrity. Supported by ORIP (T32OD011083).
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.
Potent Broadly Neutralizing Antibodies Mediate Efficient Antibody-Dependent Phagocytosis of HIV-Infected Cells
Snow et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/39466835
This study investigates the role of potent broadly neutralizing antibodies (bNAbs) in mediating antibody-dependent cellular phagocytosis (ADCP) of HIV-infected cells. Researchers developed a novel cell-based approach to assess the ADCP of HIV-infected cells expressing natural conformations of the viral envelope glycoprotein, which allows the virus to infect a host cell. The findings in this study demonstrate that bNAbs facilitate efficient ADCP, highlighting their potential in controlling HIV infection by promoting immune clearance of infected cells. This study provides valuable insights into antibody-mediated immune mechanisms and supports the development of antibody-based therapies and vaccines targeting HIV. Supported by ORIP (P51OD011106) and NIAID.
A Single-Dose Intranasal Live-Attenuated Codon Deoptimized Vaccine Provides Broad Protection Against SARS-CoV-2 and Its Variants
Liu et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39187479
Researchers developed an intranasal, single-dose, live-attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) vaccine (CDO-7N-1) using codon deoptimization. This vaccine demonstrates broad protection against SARS-CoV-2 variants, with highly attenuated replication and minimal lung pathology across multiple in vivo passages. The vaccine induced robust mucosal and systemic neutralizing antibodies, as well as T-cell responses, in male and female hamsters, female K18-hACE2 mice, and male HFH4-hACE2 mice. In male and female cynomolgus macaques, CDO-7N-1 effectively prevented infection, reduced severe disease, and limited transmission of SARS-CoV-2 variants. This innovative approach offers potential advantages over traditional spike-protein vaccines by providing durable protection and targeting emerging variants to curb virus transmission. Supported by ORIP (K01OD026529).
Extended Survival of 9- and 10-Gene-Edited Pig Heart Xenografts With Ischemia Minimization and CD154 Costimulation Blockade-Based Immunosuppression
Chaban et al., The Journal of Heart and Lung Transplantation. 2024.
https://pubmed.ncbi.nlm.nih.gov/39097214
Heart transplantations are severely constrained from the shortage of available organs derived from human donors. Xenotransplantation of hearts from gene-edited (GE) pigs is a promising way to address this problem. Researchers evaluated GE pig hearts with varying knockouts and human transgene insertions. Human transgenes are introduced to mitigate important physiological incompatibilities between pig cells and human blood. Using a baboon heterotopic cardiac transplantation model, one female and seven male specific-pathogen-free baboons received either a 3-GE, 9-GE, or 10-GE pig heart with an immunosuppression regimen targeting CD40/CD154. Early cardiac xenograft failure with complement activation and multifocal infarcts were observed with 3-GE pig hearts, whereas 9- and 10-GE pig hearts demonstrated successful graft function and prolonged survival. These findings show that one or more transgenes of the 9- and 10-GE pig hearts with CD154 blockade provide graft protection in this preclinical model. Supported by ORIP (U42OD011140) and NIAID.