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- nhlbi
- HIV/AIDS
- Neurological
Establishing the Hybrid Rat Diversity Program: A Resource for Dissecting Complex Traits
Dwinell et al., Mammalian Genome. 2025.
https://pubmed.ncbi.nlm.nih.gov/39907792
Rat models have been extensively used for studying human complex disease mechanisms, behavioral phenotypes, and environmental factors and for discovering and developing drugs. Systems genetics approaches have been used to study the effects of both genetic variation and environmental factors. This approach recognizes the complexity of common disorders and uses intermediate phenotypes to find relationships between genetic variation and clinical traits. This article describes the Hybrid Rat Diversity Program (HDRP) at the Medical College of Wisconsin, which involves 96 inbred rat strains and aims to provide a renewable and reusable resource in terms of the HRDP panel of inbred rat strains, the genomic data derived from the HRDP strains, and banked resources available for additional studies. Supported by ORIP (R24OD024617) and NHLBI.
Peripherally Mediated Opioid Combination Therapy in Mouse and Pig
Peterson et al., The Journal of Pain. 2025.
https://pubmed.ncbi.nlm.nih.gov/39542192
This study evaluates novel opioid combinations for pain relief with reduced side effects. Researchers investigated loperamide (a μ-opioid agonist) with either oxymorphindole or N‑benzyl-oxymorphindole—both δ-opioid receptor partial agonists—in mice (male and female) and pigs (male). These combinations produced synergistic analgesia across species without causing adverse effects or respiratory depression. The therapies significantly reduced hypersensitivity in post-injury models, outperforming morphine alone. These findings suggest that peripherally acting opioid combinations can offer effective, safer alternatives for pain management, potentially lowering opioid misuse and side effects. This approach could improve clinical strategies for treating chronic and acute pain with limited central opioid exposure. Supported by ORIP (T32OD010993), NHLBI, and NIDA.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
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.
Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease
Uh et al., Journal of Alzheimer's Disease. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177593/
This study explored the effects of presenilin 1 (PSEN1) disruption on vertebral malformations in male and female PSEN1 mutant pigs. Researchers observed significant skeletal impairments and early deaths in pigs with a PSEN1 null mutation, mirroring phenotypes seen in mouse models of Alzheimer’s disease (AD). This porcine model provides valuable insights into pathological hallmarks of PSEN1 mutations in AD, offering a robust platform of therapeutic exploration. The findings establish pigs as an essential translational model for AD, enabling advanced studies on pathophysiology and treatment development for human skeletal and neurological conditions. Supported by ORIP (U42OD011140), NHLBI, NIA, NIAID.
Physiologically Based Pharmacokinetic Model Validated to Enable Predictions of Multiple Drugs in a Long-Acting Drug-Combination Nano-Particles (DcNP): Confirmation With 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products
Perazzolo et al., Journal of Pharmaceutical Sciences. 2024.
https://jpharmsci.org/article/S0022-3549(24)00060-1/fulltext
Drug-combination nanoparticles synchronize delivery of multiple drugs in a single, long-acting, targeted dose. Two distinct classes of long-acting injectable products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site, and Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access. This review used data from three nonhuman primate studies, consisting of nine pharmacokinetic data sets, to support clinical development of Class II products. Eight of nine models passed validation, and the drug–drug interaction identified in the ninth model can be accounted for in the final model. Supported by ORIP (P51OD010425, U42OD011123), NIAID, and NHLBI.
Persistence of a Skewed Repertoire of NK Cells in People With HIV-1 on Long-Term Antiretroviral Therapy
Anderko et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551350
HIV-1 infection alters the natural killer (NK) cell phenotypic and functional repertoire. A rare population of FcRγ−NK cells exhibiting characteristics of traditional immunologic memory expands in people with HIV. In a longitudinal analysis during the first 4 years of antiretroviral therapy (ART), a skewed repertoire of cytokine unresponsive FcRγ−memory-like NK cells persisted in people with HIV, and surface expression of CD57 and KLRG1 increased, suggesting progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing antibody titers to human cytomegalovirus (CMV), with human CMV viremia detected in approximately one-third of people studied during the first 4 years of ART. About 40% of people studied displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis. These findings indicate that NK cell irregularities persist in people with HIV despite long-term ART. Supported by ORIP (P51OD011132, S10OD026799), NIAID, and NHLBI.
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.
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.
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.