Selected Grantee Publications
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- 257 results found
- Cancer
- Vaccines/Therapeutics
Isoniazid and Rifapentine Treatment Effectively Reduces Persistent M. tuberculosis Infection in Macaque Lungs
Sharan et al., Journal of Clinical Investigation. 2022.
https://www.doi.org/10.1172/JCI161564
People with HIV and asymptomatic latent tuberculosis (TB) coinfection are at risk of developing active TB symptoms. The Centers for Disease Control and Prevention recommends a weekly dose of isoniazid and rifapentine for 3 months (3HP) for treatment of latent TB infection, but the sterilizing efficacy of the regimen has not been demonstrated previously. Using rhesus macaques of both sexes, researchers evaluated the efficacy of the 3HP regimen in eradicating persistent Mycobacterium tuberculosis infection. They found that treatment reduced the risk of developing active TB but did not establish complete sterilization. This work establishes a new animal model for evaluating the efficacy of different drug regimens. Supported by ORIP (P51OD011133, S10OD028732).
Metabolic Transitions Define Spermatogonial Stem Cell Maturation
Voigt et al., Human Reproduction. 2022.
https://www.doi.org/10.1093/humrep/deac157
The spermatogonial stem cell (SSC) is the basis of male fertility. One potential option to preserve fertility in patients treated with anti-cancer therapy is isolation and laboratory culture of the juvenile SSC pool with subsequent transplantation to restore spermatogenesis. However, efficient culture of undifferentiated spermatogonia, including SSCs, in mammals other than rodents remains challenging. Investigators reported that the metabolic phenotype of prepubertal human spermatogonia is distinct from that of adult spermatogonia and that SSC development is characterized by specific metabolic transitions from oxidative phosphorylation to anaerobic metabolism. Supported by ORIP (R01OD016575) and NICHD.
Rbbp4 Loss Disrupts Neural Progenitor Cell Cycle Regulation Independent of Rb and Leads to Tp53 Acetylation and Apoptosis
Schultz-Rogers et al., Developmental Dynamics. 2022.
https://www.doi.org/10.1002/dvdy.467
Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression by cooperating with the Rb tumor suppressor to block cell cycle entry. The authors used genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival. Rbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers, and it is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ-H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. Rbbp4; Rb1 double mutants show an additive effect on the number of M phase cells. The study demonstrates that Rbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0, independent of Rb, and suggests that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival. Supported by ORIP (R24OD020166) and NIGMS.
A Multidimensional Metabolomics Workflow to Image Biodistribution and Evaluate Pharmacodynamics in Adult Zebrafish
Jackstadt et al., Disease Models & Mechanisms. 2022.
https://www.doi.org/10.1242/dmm.049550
The evaluation of tissue distribution and pharmacodynamic properties of a drug is essential but often expensive in clinical research. The investigators developed a multidimensional metabolomics platform to evaluate drug activity that integrates mass spectrometry–based imaging, absolute drug quantitation, in vivo isotope tracing, and global metabolome analysis in zebrafish. They validated this platform by evaluating whole-body distribution of the anti-rheumatic agent hydroxychloroquine sulfate and its impact on the systemic metabolism of adult zebrafish. This work suggests that the multidimensional metabolomics platform is a cost-effective method for evaluating on- and off-target effects of drugs. Supported by ORIP (R24OD024624) and NIEHS.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
Stromal P53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner
Wu et al., Molecular Cancer Research. 2022.
https://www.doi.org/10.1158/1541-7786.MCR-21-0960
Loss of stromal p53 function drives tumor progression in breast cancer, but the exact mechanisms have been relatively unexplored. Using mouse models, researchers demonstrated that loss of cancer-associated fibroblast (CAF) p53 enhances carcinoma formation driven by oncogenic KRAS G12D, but not ERBB2, in mammary epithelia. These results corresponded with increased tumor cell proliferation and DNA damage, as well as decreased apoptosis, in the KRAS G12D model. Furthermore, a gene cluster associated with CAF p53 deficiency was found to associate negatively with survival in microarray and heat map analyses. These data indicate that stromal p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately affects patient survival. Supported by ORIP (K01OD026527) and NCI.
Durable Protection Against the SARS-CoV-2 Omicron Variant Is Induced by an Adjuvanted Subunit Vaccine
Arunachalam et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abq4130
Additional SARS-CoV-2 vaccines are needed, owing to waning immunity to the original vaccines and the emergence of variants of concern. A recent study in male rhesus macaques demonstrated durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, an oil-in-water emulsion containing α‑tocopherol. Two immunizations with the vaccine resulted in durable immunity, without cross-reactivity. Further boosting with a version of the vaccine containing the Beta variant or the ancestral RBD elicited cross-reactive immune responses that conferred protection against Omicron challenge. Supported by ORIP (P51OD011104), NCI, and NIAID.
Sunitinib Inhibits STAT3 Phosphorylation in Cardiac Muscle and Prevents Cardiomyopathy in the mdx Mouse Model of Duchenne Muscular Dystrophy
Oliveira-Santos et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac042
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, affecting about 1 in 5,000 boys worldwide. DMD is a fatal X-linked genetic disorder that results from mutations in the dystrophin gene and leads to progressive muscular degeneration. Individuals with DMD often die at a young age from respiratory or heart failure. To date, few studies have examined the basis of cardiac failure associated with DMD, and no effective U.S. Food and Drug Administration (FDA)–approved treatment options are available. Using a mouse model of both sexes, researchers characterized the effectiveness of sunitinib, an FDA-approved small-molecule drug, in preventing DMD-related cardiomyopathy. The treatment reduced STAT3 activation in cardiac muscle and prevented cardiomyopathy disease progression. Inhibition of STAT3 activation in cardiac muscle can reduce inflammation and fibrosis and prevent heart failure. These findings demonstrate sunitinib’s potential as a novel treatment option for skeletal and cardiac muscle dysfunction in patients with DMD. Supported by ORIP (R42OD030543).
A Clade C HIV-1 Vaccine Protects Against Heterologous SHIV Infection by Modulating IgG Glycosylation and T Helper Response in Macaques
Sahoo et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abl4102
Vaccines for HIV-1 capable of generating a broadly cross-reactive neutralizing antibody response are needed urgently. The researchers tested the protective efficacy of a clade C HIV-1 vaccination regimen in male rhesus macaques. The vaccine was administered either orally using a needle-free injector or via parenteral injection. Significant protection was observed for both vaccination routes following the simian–human immunodeficiency virus (SHIV) challenge, with an estimated efficacy of 68% per exposure. The glycosylation profile of IgG and HIV-resistant helper T cell response contributes to the protection. Supported by ORIP (P51OD011132), NIAID, and NIDCR.
Allogeneic MHC‑Matched T‑Cell Receptor Α/Β‑Depleted Bone Marrow Transplants in SHIV‑Infected, ART‑Suppressed Mauritian Cynomolgus Macaques
Weinfurter et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-16306-z
Allogeneic hematopoietic stem cell transplants are effective in reducing HIV reservoirs following antiretroviral therapy (ART). A better understanding of this mechanism could enable the development of safer and more efficacious HIV treatment regimens. In this study, the researchers used a Mauritian cynomolgus macaque model to study the effects of allogeneic major histocompatibility complex–matched α/β T cell–depleted bone marrow cell transplantation following infection with simian–human immunodeficiency virus (SHIV). The macaques began ART 6 to 16 weeks post-infection. In three of the four macaques, SHIV DNA was undetectable in blood but persisted in other tissues. These results suggest that extended ART likely is needed to eradicate the HIV reservoir following transplantation. In future studies, full donor engraftment should be balanced with suppression of graft-versus-host disease. Supported by ORIP (P51OD011106, R24OD021322), and NCI.