Selected Grantee Publications
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- Nonhuman Primate Models
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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.
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.
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.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.