Skip to main content

Filter Search Results

Publication Year

Animal Models

Topic Area

Methods

Funding Mechanism

Division of Comparative Medicine

Division of Construction and Instruments

Collaborating ICs

Selected Grantee Publications

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.

Effect of Metabolic Status on Response to SIV Infection and Antiretroviral Therapy in Nonhuman Primates

Webb et al., JCI Insight. 2024.

https://pubmed.ncbi.nlm.nih.gov/39115937

This study examines how metabolic health influences the efficacy of antiretroviral therapy (ART). Using lean and obese male rhesus macaques, researchers explored the progression of simian immunodeficiency virus (SIV) infection. Obese macaques with metabolic dysfunction experienced more rapid disease progression and had a diminished response to ART than lean macaques. This study suggests metabolic health plays a significant role in HIV progression and treatment outcomes, highlighting the importance of managing metabolic conditions in people with HIV. Supported by ORIP (P51OD011092, S10OD025002), NIAID, and NIDDK.

Systematic Multi-trait AAV Capsid Engineering for Efficient Gene Delivery

Eid et al., Nature Communications. 2024.

https://doi.org/10.1038/s41467-024-50555-y

Engineering novel functions into proteins while retaining desired traits is a key challenge for developers of viral vectors, antibodies, and inhibitors of medical and industrial value. In this study, investigators developed Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait adeno-associated virus (AAV) capsids. Fit4Function was used to generate reproducible screening data from a capsid library that samples the entire manufacturable sequence space. The Fit4Function data were used to train accurate sequence-to-function models, which were combined to develop a library of capsid candidates. Compared to AAV9, top candidates from the Fit4Function capsid library exhibited comparable production yields; more efficient murine liver transduction; up to 1,000-fold greater human hepatocyte transduction; and increased enrichment in a screen for liver transduction in macaques. The Fit4Function strategy enables prediction of peptide-modified AAV capsid traits across species and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits. Supported by ORIP (P51OD011107, U42OD027094), NIDDK, NIMH, and NINDS.

Anti–PD-1 Chimeric Antigen Receptor T Cells Efficiently Target SIV-Infected CD4+ T Cells in Germinal Centers

Eichholtz et al., The Journal of Clinical Investigation. 2024.

https://pubmed.ncbi.nlm.nih.gov/38557496/

Researchers conducted adoptive transfer of anti–programmed cell death protein 1 (PD-1) chimeric antigen receptor (CAR) T cells in simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes on antiretroviral therapy (ART). In some macaques, anti–PD-1 CAR T cells expanded and persisted concomitant with the depletion of PD-1+ memory T cells—including lymph node CD4+ follicular helper T cells—associated with depletion of SIV RNA from the germinal center. Following CAR T infusion and ART interruption, SIV replication increased in extrafollicular portions of lymph nodes, plasma viremia was higher, and disease progression accelerated, indicating that anti–PD-1 CAR T cells depleted PD-1+ T cells and eradicated SIV from this immunological sanctuary. Supported by ORIP (U42OD011123, U42OD010426, P51OD010425, P51OD011092), NCI, NIAID, and NIDDK.

SHIV-C109p5 NHP Induces Rapid Disease Progression in Elderly Macaques with Extensive GI Viral Replication

Bose et al., Journal of Virology. 2024.

https://pubmed.ncbi.nlm.nih.gov/38299866/

Researchers are interested in developing animal models infected with simian–human immunodeficiency virus (SHIV) to better understand prevention of HIV acquisition. Researchers generated pathogenic SHIV clade C transmitted/founder stock by in vivo passage using geriatric rhesus macaques of both sexes. They reported that the infection resulted in high sustained viral loads and induced rapid pathology and wasting, necessitating euthanasia between 3 and 12 weeks post-infection. The extensive viral replication in gut and lymphoid tissues indicated a fit viral stock. This work provides a new nonhuman primate model for HIV pathogenicity and cure studies. Supported by ORIP (R24OD010947) and NIDDK.