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- Cardiovascular
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.
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.
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.
Pigs in Transplantation Research and Their Potential as Sources of Organs in Clinical Xenotransplantation
Raza et al., Comparative Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38359908/
The pig has now gained importance as a potential source of organs for clinical xenotransplantation. When an organ from a wild-type (i.e., genetically unmodified) pig is transplanted into an immunosuppressed nonhuman primate, a vigorous host immune response causes hyperacute rejection (within minutes or hours). This response has been largely overcome by (1) extensive gene editing of the organ-source pig and (2) administration to the recipient of novel immunosuppressive therapy based on blockade of the CD40/CD154 T-cell costimulation pathway. The combination of gene editing and novel immunosuppressive therapy has extended life-supporting pig kidney graft survival to greater than 1 year and of pig heart survival to up to 9 months. This review briefly describes the techniques of gene editing, the potential risks of transfer of porcine endogenous retroviruses with the organ, and the need for breeding and housing of donor pigs under biosecure conditions. Supported by ORIP (P40OD024628) and NIAID.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28- CD8 T Cells in HIV Infection and Atherosclerosis via the CD2–LFA-3 Axis
Winchester et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38047900/
People with HIV are at increased risk of developing atherosclerosis and other cardiovascular diseases, and HIV coinfection with cytomegalovirus (CMV) is associated with immune activation and inflammation. In this study, researchers explored the role of the CD2–LFA-3 axis in driving activation and proliferation of CD57+CD28- CD8 T cells using clinical samples from patients with or without HIV. They propose a model in which CMV infection is linked to enhanced CD2 expression on the T cells, enabling the activation via LFA-3 signals and potentially leading to cardiopathogenic interactions with vascular endothelial cells that express LFA-3. This work provides a potential therapeutic target in atherosclerosis development and progression, especially for people with HIV. Supported by ORIP (P51OD011132, U24OD011023) and NIAID.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Recreating the Heart’s Helical Structure–Function Relationship With Focused Rotary Jet Spinning
Chang et al., Science. 2022.
https://www.doi.org/10.1126/science.abl6395
The investigators developed a tissue engineering approach that enables rapid deposition of cardiomyocyte microfibers with programmable alignments in 3D geometries. Using this focused rotary jet spinning (FRJS) method, they reproduced tissue scaffolds with contractile cells' helical alignments, resembling complex structures of the musculature and properties of a natural heart. This work represents an important advance towards biofabrication of tissue models for healthy and diseased hearts by manipulating orientation of specific fibers. With the technological advancement over other competing methods, FRJS might provide a pathway towards fabricating other tissues and organs with diverse cell populations. Supported by ORIP (S10OD023519) and NCATS.