Selected Grantee Publications
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- 9 results found
- COVID-19/Coronavirus
- Somatic Cell Genome Editing
- 2024
A Single-Dose Intranasal Live-Attenuated Codon Deoptimized Vaccine Provides Broad Protection Against SARS-CoV-2 and Its Variants
Liu et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39187479
Researchers developed an intranasal, single-dose, live-attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) vaccine (CDO-7N-1) using codon deoptimization. This vaccine demonstrates broad protection against SARS-CoV-2 variants, with highly attenuated replication and minimal lung pathology across multiple in vivo passages. The vaccine induced robust mucosal and systemic neutralizing antibodies, as well as T-cell responses, in male and female hamsters, female K18-hACE2 mice, and male HFH4-hACE2 mice. In male and female cynomolgus macaques, CDO-7N-1 effectively prevented infection, reduced severe disease, and limited transmission of SARS-CoV-2 variants. This innovative approach offers potential advantages over traditional spike-protein vaccines by providing durable protection and targeting emerging variants to curb virus transmission. Supported by ORIP (K01OD026529).
Characterization of Collaborative Cross Mouse Founder Strain CAST/EiJ as a Novel Model for Lethal COVID-19
Baker et al., Scientific Reports. 2024.
https://www.nature.com/articles/s41598-024-77087-1
Researchers characterized the Collaborative Cross (CC) mouse model founder strain CAST/EiJ as a novel model for severe COVID-19, exhibiting high viral loads and mortality. By leveraging genetically diverse CC strains, this study identified variations in susceptibility and survival against SARS-CoV-2 variants. CAST/EiJ mice developed lung pathology and mortality despite antiviral defenses, making them a valuable tool for understanding host–pathogen interactions. The findings emphasize the utility of diverse animal models in uncovering genetic and immunological factors that influence disease outcomes, facilitating the development of targeted therapies against COVID-19 to mitigate future pandemics. Supported by ORIP (P40OD011102).
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
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.
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.
Engineered IgM and IgG Cleaving Enzymes for Mitigating Antibody Neutralization and Complement Activation in AAV Gene Transfer
Smith et al., Molecular Therapy. 2024.
https://www.sciencedirect.com/science/article/pii/S1525001624003058?via%3Dihub=
Recombinant adeno-associated viral (AAV) vectors have emerged as the leading platform for therapeutic gene transfer, but systemic dosing of AAV vectors poses potential risk of adverse side effects, including complement activation triggered by anti-capsid immunity. In this study, investigators discovered an IgM cleaving enzyme (IceM) that degrades human IgM, a key trigger in the anti-AAV immune cascade. They engineered a fusion enzyme (IceMG) with dual proteolytic activity against human IgM and IgG. Antisera from animals treated with IceMG show decreased ability to neutralize AAV and activate complement. These studies have implications for improving the safety of AAV gene therapies and offer broader applications, including for organ transplantation and autoimmune diseases. Supported by ORIP (P51OD011107, U42OD027094), NHLBI, and NIAID.
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
Pathogenesis and Virulence of Coronavirus Disease: Comparative Pathology of Animal Models for COVID-19
Kirk et al., Virulence. 2024.
https://pubmed.ncbi.nlm.nih.gov/38362881
Researchers have used animal models that can replicate clinical and pathologic features of severe human coronavirus infections to develop novel vaccines and therapeutics in humans. The purpose of this review is to describe important animal models for COVID-19, with an emphasis on comparative pathology. The highlighted species included mice, ferrets, hamsters, and nonhuman primates. Knowledge gained from studying these animal models can help inform appropriate model selection for disease modeling, as well as for vaccine and therapeutic developments. Supported by ORIP (T32OD010993) and NIAID.
Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population
Cruz Cisneros et al., Vaccines. 2024.
https://pubmed.ncbi.nlm.nih.gov/38276675/
The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. Although host genetic factors are known to affect vaccine efficacy for such respiratory pathogens as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. Investigators used the diversity outbred mouse model to study the effects of genetic variation on vaccine efficiency. Data indicate that variations in vaccine response in mice are heritable, similar to that in human populations. Supported by ORIP (U42OD010924), NIAID, and NIGMS.