Selected Grantee Publications
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- 46 results found
- Nonhuman Primate Models
- Cardiovascular
- Neurological
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.
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.
A Switch from Glial to Neuronal Gene Expression Alterations in the Spinal Cord of SIV-Infected Macaques on Antiretroviral Therapy
Mulka et al., Journal of Neuroimmune Pharmacology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38862787/
Up to one-third of patients with HIV experience HIV-associated peripheral neuropathy, affecting sensory pathways in the spinal cord. Spinal cord sampling is limited in people with HIV. Researchers examined gene expression alterations in the spinal cords of simian immunodeficiency virus (SIV)-infected male pigtail macaques with and without antiretroviral therapy (ART), using RNA sequencing at key time points throughout infection. Results indicate a shift from glial cell-associated pathways to neuronal pathways in SIV-infected animals receiving ART. These findings suggest that neurons, rather than glia, are predominantly involved in ART-related neurotoxicity and offer new insights into therapeutic strategies for maintaining synaptic homeostasis. Supported by ORIP (U42OD013117, T32OD011089) and NINDS.
Transcriptomic and Genetic Profiling in a Spontaneous Non-Human Primate Model of Hypertrophic Cardiomyopathy and Sudden Cardiac Death
Rivas et al., Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39733099/
Approximately 1 in 500 individuals are affected by hypertrophic cardiomyopathy (HCM). HCM is characterized by increased left ventricular wall thickness, diastolic dysfunction, and myocardial fibrosis. Outcomes of HCM range from arrhythmias and thromboembolic complications to sudden cardiac death. A current knowledge gap is in understanding the genetic cause of HCM. Researchers compared a nonhuman primate rhesus macaque HCM model to an adult human cohort data set and found that they shared 215 upregulated differentially expressed genes (DEGs); 40 downregulated DEGs; and enriched gene ontology terms, including cardiac muscle cell contraction and heart contraction. The molecular similarity in transcriptomic signatures could be used to develop novel drug therapies to treat HCM in patients. Supported by ORIP (P51OD011107, T32OD011147), NCATS, and NHLBI.
SIV-Specific Antibodies Protect Against Inflammasome-Driven Encephalitis in Untreated Macaques
Castell et al., Cell Reports. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11552693
Viral infections are the most common infectious cause of encephalitis, and simian immunodeficiency virus (SIV)–infected macaques are a well-established model for HIV. Researchers investigated the protective effects of SIV-specific antibodies against inflammation-driven encephalitis in using untreated, SIV-infected, male and female pigtail and rhesus macaques. Findings indicate that these antibodies reduce neuroinflammation and encephalitis, highlighting the importance of antibodies in controlling neuroimmune responses, especially in the absence of antiretroviral therapy. This study provides insight into immune-modulatory approaches to combating inflammation-driven encephalopathies. Supported by ORIP (U42OD013117, T32OD011089), NIDA, NHLBI, NIAID, NINDS, and NIMH.
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.
Human Stem Cell-Derived Cardiomyocytes Integrate Into the Heart of Monkeys With Right Ventricular Pressure Overload
Scholz et al., Cell Transplantation. 2024.
https://journals.sagepub.com/doi/10.1177/09636897241290367
Patients with single-ventricle congenital heart defects suffer from right ventricular pressure overload (RVPO). Researchers developed a novel pulmonary artery banding (PAB) rhesus macaque model to induce RVPO. This study investigated the efficacy of human induced pluripotent stem cell cardiac lineage cell (hiPSC-CL) delivery at low or high dose into adult male and female rhesus macaques with right ventricular dysfunction. The findings indicate that hiPSC-CLs were successfully grafted and integrated to match the surrounding host right ventricle myocardium. These results suggest hiPSC-CL therapy is a potential adjunctive treatment for RVPO, but future research will be needed to elucidate the beneficial effects. Supported by ORIP (P51OD011106).
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.
Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Tisoncik-Go et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49524-2
Maternal infection during pregnancy can have severe consequences on fetal development and survival. Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. This study suggests that reduced myelin resulting from Zika infection in utero is likely a contributing factor to severe deficits in brain development and microcephaly. Supported by ORIP (P51OD010425), NEI, and NIAID.