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- Cardiovascular
- Pediatrics
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).
Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome
Lloyd, Mammalian Genome. 2024.
https://pubmed.ncbi.nlm.nih.gov/39254744
The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).
The Mutant Mouse Resource and Research Center (MMRRC) Consortium: The U.S.-Based Public Mouse Repository System
Agca et al., Mammalian Genome. 2024.
https://link.springer.com/article/10.1007/s00335-024-10070-3
The MMRRC has been the nation’s preeminent public repository and distribution archive of mutant mouse models for 25 years. The Consortium, with support from NIH, facilitates biomedical research by identifying, acquiring, evaluating, characterizing, preserving, and distributing a variety of mutant mouse strains to investigators around the world. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8,441 institutions worldwide. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem-cell lines, and murine monoclonal antibodies for nearly 65,000 alleles. The Consortium also provides scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, husbandry, breeding and colony management, and more. Supported by ORIP (U42OD010918, U42OD010924, U42OD010983).
Sex-Specific Cardiac Remodeling in Aged Rats After Adolescent Chronic Stress: Associations with Endocrine and Metabolic Factors
Dearing et al., Biology of Sex Differences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39180122
Cardiovascular disease is a leading cause of death in the world. The potential effects of chronic stress on the development and progression of cardiovascular disease in the aged heart are unknown. In this study, researchers investigated sex- and stress-specific effects on left ventricular hypertrophy (LVH) after aging. Male and female rats were exposed to chronic stress during adolescence and then challenged with a swim test and a glucose tolerance test before and after aging 15 months. As a group, female rats showed increased LVH in response to early life stress. Male rats showed individual differences in vulnerability. These results indicate that sex and stress history can interact to determine susceptibility to cardiovascular risks. Supported by ORIP (F30OD032120, T35OD015130) and NHLBI.
Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Nelson et al., Science Immunology. 2024.
https://www.science.org/doi/10.1126/sciimmunol.adm7097
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env—SOSIP—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut. Supported by ORIP (P51OD011107), NCI, and NIAID.
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.
AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys
Liang et al., Human Gene Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38767512/
Genome editing in somatic cells and tissues has the potential to provide long-term expression of therapeutic proteins to treat a variety of genetic lung disorders. However, delivering genome-editing machinery to disease-relevant cell types in the lungs of primates has remained a challenge. Investigators of this article are participating in the NIH Somatic Cell Genome Editing Consortium. Herein, they demonstrate that intratracheal administration of a dual adeno-associated virus type 5 vector encoding CRISPR/Cas9 can mediate genome editing in rhesus (male and female) airways. Up to 8% editing was observed in lung lobes, including a housekeeping gene, GAPDH, and a disease-related gene, angiotensin-converting enzyme 2. Using single-nucleus RNA-sequencing, investigators systematically characterized cell types transduced by the vector. Supported by ORIP (P51OD01110, U42OD027094, S10OD028713), NCATS, NCI, and NHLBI.
Functional and Structural Basis of Human Parainfluenza Virus Type 3 Neutralization With Human Monoclonal Antibodies
Suryadevara et al., Nature Microbiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38858594
Human parainfluenza virus type 3 (hPIV3) can cause severe disease in older people and infants, and the haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Researchers isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. They also delineated the structural basis of neutralization for HN and F monoclonal antibodies (mAbs). Rats were protected against infection and disease in vivo by mAbs that neutralized hPIV3 in vitro. This work establishes correlates of protection for hPIV3 and highlights the potential clinical utility of mAbs. Supported by ORIP (K01OD036063), NIAID, and NIGMS.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
Natural Killer–Like B Cells Are a Distinct but Infrequent Innate Immune Cell Subset Modulated by SIV Infection of Rhesus Macaques
Manickam et al., PLOS Pathogens. 2024.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012223
Natural killer–like B (NKB) cells express both natural killer (NK) and B cell receptors. Intracellular signaling proteins and trafficking markers were expressed differentially on naive NKB cells. CD20+ NKG2A/C+ NKB cells were identified in organs and lymph nodes of naive rhesus macaques (RMs). Single-cell RNA sequencing (scRNAseq) of sorted NKB cells confirmed that NKB cells are unique, and transcriptomic analysis of naive splenic NKB cells by scRNAseq showed that NKB cells undergo somatic hypermutation and express Ig receptors, similar to B cells. Expanded NKB frequencies were observed in RM gut and buccal mucosa after simian immunodeficiency virus (SIV) infection, and mucosal and peripheral NKB cells were associated with colorectal cytokine milieu and oral microbiome changes. NKB cells gated on CD3-CD14-CD20+NKG2A/C+ cells were inclusive of transcriptomically conventional B and NK cells in addition to true NKB cells, confounding accurate phenotyping and frequency recordings. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.