Biology subjects

Lai, Y.-T.

Publications and source records attributed to Lai, Y.-T..

6 recordsLinked to original sources

bioRxiv2025

A multivalent mRNA-LNP therapeutic vaccine with broad cross-genotype immunogenicity elicits clearance of HBV infected hepatocytes

Chronic hepatitis B remains a major global health challenge, affecting over 254 million individuals and causing over 1 million deaths annually. Despite current antiviral therapies effectively suppressing viral replication, functional cure rates are low due to HBV-induced immune dysfunction and exhaustion. Therefore, new therapeutic approaches to achieve immune control of HBV infection are needed. Following the systematic evaluation of multiple HBV mRNA antigen designs, we developed mRNA-1965, a trivalent therapeutic mRNA vaccine encoding nanoparticle-displayed PreS1 and PreS2 domains of HBsAg to bypass the immune interference caused by HBV subviral particles, along with mutant forms of HBV Core and Polymerase. In HBV naive mice, mRNA-1965 immunization induced dose-dependent HBV-neutralizing antibodies and Th1-skewed CD4+ and IFN{gamma}+ CD8+ T cell responses to all three encoded HBV antigens. In non-human primates, mRNA-1965 elicited broad antibody and T cell responses across multiple HBV genotypes. Furthermore, vaccination with mRNA-1965 achieved a strong neutralizing antibody response and complete clearance of serum and liver HBV biomarkers in in an AAV-HBV mouse model with [~]100 IU/mL baseline HBsAg. Notably, combining mRNA-1965 with immune stimulatory co-modalities targeting PD-L1 and OX40 further enhanced therapeutic efficacy in mice with [~]1000 IU/mL baseline HBsAg. Clearance of HBV in AAV-HBV mice was associated with T cell response to mRNA-encoded antigens and with activation and differentiation of Core-specific CD8+ T cells. These findings support the potential of mRNA-1965 to promote a functional cure for chronic hepatitis B by overcoming immune dysfunction and subsequently enabling robust, functional immunity.

immunology↗

bioRxiv2023

mRNA delivery of dimeric human IgA protects mucosal tissues from bacterial infection

Monoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is limited to IgG1 isotypes that have restricted access to mucosal sites. IgA is well-established as the predominant antibody isotype in mucosal secretions but is clinically underutilized. To enable development of IgA-based mAbs, we exploited mRNA platform technology and demonstrated expression of functional, antigen-specific IgA (IgAmRNA) that can limit bacterial invasion in the intestine and prevent colonization in the lung. Moreover, in vivo IgAmRNA had enhanced serum half-life and a greater degree of sialylation than a recombinantly produced IgA. The results underscore the potential of mRNA-based platforms to deliver protective human mAbs to mucosal surfaces and open new avenues to combat infectious diseases in the face of pervasive antibiotic resistance. One Sentence SummarymRNA-encoded human monoclonal IgA traffics to mucosal tissues and provides protection against bacterial challenge

immunology↗

bioRxiv2022

The Drosophila AWP1 ortholog Doctor No regulates JAK/STAT signaling for left-right asymmetry in the gut by promoting receptor endocytosis

Many internal Drosophila organs show stereotypical left-right (LR) asymmetry, for which the underlying mechanisms remain elusive. Here, we identified an evolutionarily conserved ubiquitin-binding protein, AWP1/Doctor no (Drn), as a novel factor required for the LR asymmetry of the embryonic anterior gut in Drosophila. We showed that drn is essential in the circular visceral muscle cells of the midgut for JAK/STAT signaling, which contributes to the first known cue for anterior gut lateralization via LR-asymmetric nuclear rearrangement. Embryos homozygous for drn and lacking its maternal contribution showed phenotypes similar to that of depleted JAK/STAT signaling, suggesting that Drn is a general component of JAK/STAT signaling. The absence of Drn resulted in the specific accumulation of Domeless (Dome), the receptor of JAK/STAT signaling, in intracellular compartments. Thus, Drn is required for the endocytic trafficking of Dome, which is subsequently degraded in lysosomes. Our results suggest that the endocytosis of Dome is a critical step in activating JAK/STAT signaling. The roles of AWP1/Drn in activating JAK/STAT signaling and in LR-asymmetric development may be conserved in various organisms. Summary StatementDr. No, a Drosophila ortholog of AWP1, activates JAK/STAT signaling via Dome receptor endocytosis in a crucial step for left-right asymmetry in the developing gut.

developmental biology↗

bioRxiv2022

The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments

Numerous tau immunotherapies are being developed against Alzheimers disease (AD), but it has been challenging to specifically target early-stage tau aggregates using conformation-dependent antibodies. Here, we report a monoclonal antibody, APNmAb005, that recognized a conformational epitope associated with tau oligomers. In AD brain extracts, mAb005 preferentially recognized oligomeric tau in the synapse over monomeric tau in the cytosol. In the prefrontal cortex and hippocampus, mAb005 immunoreactivity was strongly present in early-stage AD but surprisingly diminished in late-stage AD (Braak stage VI). mAb005 also recognized aggregates in 3R tauopathies (Picks disease) and 4R tauopathies (corticobasal degeneration and progressive supranuclear palsy), including those in astrocytes and oligodendrocytes. In rTg4510 mice (P301L tau), mAb005 immunoreactivity first appeared in distal neurites but much later in neuronal somas. Thus, the mAb005 epitope appears to be associated with early-stage oligomers of tau (esoTau) that accumulate around synapses in AD, which is also detectable in both 3R and 4R tauopathies. In cellular uptake models of tauopathy transmission, mAb005 blocked the formation of intracellular inclusions induced by incubation with rTg4510 mouse brain extracts. Long-term treatments with mAb005 in rTg4510 mice partially rescued synaptic and neuronal loss in the hippocampus without promoting overall tau clearance. Our data suggest that immunotherapies targeting esoTau enriched around synaptic sites may alleviate tau toxicity against synapses and neurons, which may be a promising treatment strategy against AD. One Sentence SummaryA tau-conformer antibody recognizing synaptic oligomers and 3R, 4R, and mixed aggregates in humans rescues neuronal loss in mouse tauopathy models.

neuroscience↗

bioRxiv2018

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

A central goal of HIV-1-vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion-stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryo-electron microscopy structures of these antibodies revealed fusion peptide-conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses suggesting translatability. The N terminus of the HIV-1-fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

immunology↗

bioRxiv2017

Enhancer identification and activity evaluation in the red flour beetle, Tribolium castaneum

Evolution of cis-properties (such as enhancers) often plays an important role in the production of diverse morphology. However, a mechanistic understanding is often limited by the absence of methods to study enhancers in species outside of established model systems. Here, we sought to establish methods to identify and test enhancer activity in the red flour beetle, Tribolium castaneum. To identify possible enhancer regions, we first obtained genome-wide chromatin profiles from various tissues and stages of Tribolium via FAIRE (Formaldehyde Assisted Isolation of Regulatory Elements)-sequencing. Comparison of these profiles revealed a distinct set of open chromatin regions in each tissue and stage. Second, we established the first reporter assay system that works in both Drosophila and Tribolium, using nubbin in the wing and hunchback in the embryo as case studies. Together, these advances will be useful to study the evolution of cis-language and morphological diversity in Tribolium and other insects.

developmental biology↗