Selected Grantee Publications
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- 23 results found
- Vaccines/Therapeutics
- P40
Investigation of Monoclonal Antibody CSX-1004 for Fentanyl Overdose
Bremer et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/38052779/
The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl and has led to more than 70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, the authors present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice, CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Using a highly translational nonhuman primate model for respiratory depression, they demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3–4 weeks. These data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose. Supported by ORIP (P40OD010938) and NIDA.
CD8+ Cells and Small Viral Reservoirs Facilitate Post-ART Control of SIV Replication in M3+ Mauritian Cynomolgus Macaques Initiated on ART Two Weeks Post-Infection
Harwood et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10553806/
A rare group of people infected with HIV can achieve sustainable HIV remission after antiretroviral therapy (ART) withdrawal, but the underlying mechanisms are not understood fully. A team of investigators observed post-treatment control in a cohort of male cynomolgus macaques that were initiated on ART 2 weeks post-infection. Additionally, they reported that the cynomolgus macaques had smaller acute reservoirs than similarly infected rhesus macaques. Collectively, these data suggest that a combination of small reservoirs and immune-mediated virus suppression contributes to post-treatment control in cynomolgus macaques. This model could be used in future studies to develop therapeutic interventions. Supported by ORIP (P51OD011106, P40OD028116), NIAID, and NCI.
Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge With Simian-Tropic HIV
Swanstrom et al., eBioMedicine. 2023.
https://doi.org/10.1016/j.ebiom.2023.104764
Pre-exposure prophylaxis (PrEP) is effective in preventing new HIV infections, but regimen adherence remains a challenge. Antiretrovirals with long-acting pharmacokinetic properties could help overcome this limitation. Researchers examined the protective efficacy of lenacapavir, a first-in-class HIV capsid inhibitor, using male pigtail macaques. They reported that a single administration of the drug provided protection from simian-tropic HIV infection. These data demonstrate the value of this nonhuman primate model and support the clinical development of long-acting lenacapavir for PrEP in humans. Future studies could further explore and refine the drug exposure–efficacy relationship. Supported by ORIP (P40OD028116), NIAID, and NCI.
Effect of the Snake Venom Component Crotamine on Lymphatic Endothelial Cell Responses and Lymph Transport
Si et al., Microcirculation. 2023.
https://onlinelibrary.wiley.com/doi/10.1111/micc.12775
The pathology of snake envenomation is closely tied to the severity of edema in the tissue surrounding the area of the bite. This study focused on one of the most abundant venom components in North American viper venom, crotamine, and the effects it has on the cells and function of the lymphatic system. The authors found that genes that encode targets of crotamine are highly present in lymphatic tissues and cells and that there is a differential distribution of those genes that correlates with phasic contractile activity. They found that crotamine potentiates calcium flux in human dermal lymphatic endothelial cells in response to stimulation with histamine and shear stress—but not alone—and that it alters the production of nitric oxide in response to shear, as well as changes the level of F-actin polymerization of those same cells. Crotamine alters lymphatic transport of large molecular weight tracers to local lymph nodes and is deposited within the node, mostly in the immediate subcapsular region. Results suggest that snake venom components may have an impact on the function of the lymphatic system and provide new targets for improved therapeutics to treat snakebites. Supported by ORIP (P40OD010960).
A Live Dengue Virus Vaccine Carrying a Chimeric Envelope Glycoprotein Elicits Dual DENV2–DENV4 Serotype-Specific Immunity
Young et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/36914616/
Dengue vaccine development is challenging because some virus-specific antibodies are protective, whereas others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to induce balanced protective immunity. To simplify live-virus vaccine design, investigators identified co-evolutionary constraints inherent in flavivirus virion assembly. They found that the chimeric virus replicated efficiently in vitro and in vivo and that a single inoculation induced type-specific neutralizing antibodies in male macaques. These findings can be applied to the development of bivalent live dengue vaccines that induce independent immunity to multiple serotypes. Supported by ORIP (P40OD012217) and NIAID.
HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
Voss et al., Frontiers in Cell and Development Biology. 2021.
https://pubmed.ncbi.nlm.nih.gov/35036404/
New patterns of gene expression are enacted and regulated during tissue regeneration. Romidepsin, an FDA-approved HDAC inhibitor, potently blocks axolotl embryo tail regeneration by altering initial transcriptional responses to injury. Regeneration inhibitory concentrations of romidepsin increased and decreased the expression of key genes. Single-nuclei RNA sequencing at 6 HPA illustrated that key genes were altered by romidepsin in the same direction across multiple cell types. These results implicate HDAC activity as a transcriptional mechanism that operates across cell types to regulate the alternative expression of genes that associate with regenerative success versus failure outcomes. Supported by ORIP (P40OD019794, R24OD010435, R24OD021479), NICHD, and NIGMS.
Negative Inotropic Mechanisms of β-cardiotoxin in Cardiomyocytes by Depression of Myofilament ATPase Activity without Activation of the Classical β-Adrenergic Pathway
Lertwanakarn et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-00282-x
Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms of β-CTX as a β-blocker and its association with the β-adrenergic pathway. Healthy Sprague Dawley rats were used for cardiomyocytes isolation. In summary, the negative inotropic mechanism of β-CTX was discovered. β-CTX exhibits an atypical β-blocker mechanism. These properties of β-CTX may benefit in developing a novel agent aid to treat hypertrophic cardiomyopathy. Supported by ORIP (P40OD010960) and NHLBI.
CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques
Sarkar et al., Frontiers in Immunology. 2021.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.757811/full
Researchers investigated the humoral response in vaccinated rhesus macaques with CD4+ T cell depletion, using the VC10014 DNA protein co-immunization vaccine platform (with gp160 plasmids and gp140 trimeric proteins derived from an HIV-1 infected subject). Both CD4+-depleted and non-depleted animals developed comparable Tier 1 and 2 heterologous HIV-1 neutralizing plasma antibody titers. Thus, primates generate HIV neutralizing antibodies in the absence of robust CD4+ T cell help, which has important implications for vaccine development. Supported by ORIP (P51OD011092, P40OD028116, U42OD023038, U42OD010426), NIAID, and NIDCR.
Multiplexed Drug-Based Selection and Counterselection Genetic Manipulations in Drosophila
Matinyan et al., Cell Reports. 2021.
https://www.cell.com/cell-reports/pdf/S2211-1247(21)01147-5.pdf
Many highly efficient methods exist which enable transgenic flies to contribute to diagnostics and therapeutics for human diseases. In this study, researchers describe a drug-based genetic platform with four selection and two counterselection markers, increasing transgenic efficiency by more than 10-fold compared to established methods in flies. Researchers also developed a plasmid library to adapt this technology to other model organisms. This highly efficient transgenic approach significantly increases the power of not only Drosophila melanogaster but many other model organisms for biomedical research. Supported by ORIP (P40OD018537, P40OD010949, R21OD022981), NCI, NHGRI, NIGMS, and NIMH.
Blocking α4β7 Integrin Delays Viral Rebound in SHIVSF162P3-Infected Macaques Treated with Anti-HIV Broadly Neutralizing Antibodies
Frank et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abf7201
To explore therapeutic potentials of combining anti-HIV broadly neutralizing antibodies (bNAbs) with α4β7 integrin blockade using the monoclonal antibody Rh-α4β7, investigators treated SHIVSF162P3-infected, viremic macaques with bNAbs only or bNAbs and Rh-α4β7. Treatment with bNAbs alone decreased viremia below 200 copies/ml in eight out of eight macaques, but seven of the monkeys rebounded within 3 weeks. In contrast, three of six macaques treated with both Rh-α4β7 and bNAbs maintained viremia below 200 copies/ml for 21 weeks, whereas three of those monkeys rebounded after 6 weeks. These findings suggest that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques. Supported by ORIP (P51OD011104, U42OD010568, U42OD024282, P40OD028116), NIAID, and NCI.