Project description:We have developed a composite infection vaccine technology (ciVAX) assembled from approved products for rapid response to pandemics and biothreat agents. ciVAX consists of an injectable biomaterial scaffold containing factors that recruit, reprogram and release dendritic cells (DC) in vivo. For bacterial infections, ciVAX contains Fc-Mannose-Binding Lectin (FcMBL) microbeads with captured PAMPs fractions from inactivated bacterial cell-wall lysates. ciVAX vaccination generates potent humoral and T cell responses to bacterial antigens, and ciVAX protects mice and pigs against lethal E coli challenge in sepsis and septic shock models
Project description:Interventions: Dendritic cell-based cancer vaccination;Cancer, dendritic cell, vaccination
Primary outcome(s): Safety (adverse reactions, severe adverse events)
Study Design: single arm study,open(masking not used),uncontrolled control,single assignment
Project description:Endosomal escape is a central barrier to efficient nucleic acid delivery by lipid nanoparticles (LNPs) and remains challenging to quantify in vivo. We report a library of branched ionizable phospholipids (BiPs) that markedly enhance mRNA delivery to the liver. The lead candidate BiP-20 outperformed the clinical benchmark LP01 by 4-fold for CRISPR–Cas9 editing of the TTR gene at low dose with rapid pharmacokinetics. To quantify the endosomal escape kinetics of BiP-20, we used LysoTag mice, which allow immunoisolation of liver lysosomes, and our Lysosomal Barcoding method, finding that ~9% of BiP-20 LNPs reach the cytosol within 30 minutes of administration. Lysosomal proteomics revealed mechanistic regulators of escape and BiP-20–induced alterations in endosomal maturation and recycling pathways. Loss of Rab7, a mediator of late endosomal maturation, increased LNP escape. These findings provide a potent class of ionizable lipids for RNA delivery, a method to quantify endosomal escape in vivo, and mechanistic insight into the endolysosomal determinants of LNP trafficking.
Project description:The aim of this study is to evaluate the immunogenicity and clinical efficacy of intradermal vaccination with autologous RNA-modified dendritic cells (DCs) - engineered to express the WT1 protein - in patients with limited spread metastatic solid tumors, i.e. breast cancers, glioblastoma grade IV, sarcomas, malignant mesothelioma and colorectal tumors. Based on the results of our previously performed phase I study with autologous WT1 mRNA-transfected DC, the investigators hypothesize that the vaccination with DC will be well-tolerated and will result in an increase in WT1-specific CD8+ T cell responses.
| 2101939 | ecrin-mdr-crc
Project description:Combinatorial synthesis of biodegradable branched ionizable lipids for mRNA delivery and gene editing
Project description:Mass spectrometry lipidomics dataset analyzing degradation pathways of ionizable lipids in mRNA lipid nanoparticles (LNPs) exposed to environmental stressors. UHPLC–TIMS-TOF MS was used to characterize lipid oxidation products and structural degradation of DLin-MC3-DMA (MC3), SM-102, and ALC-0315 under UV irradiation, oxidative conditions, thermal exposure, and freeze–thaw cycling.
Project description:Lei et al. screen out Lactococcus lactis OMVs (Lac-OMVs) and develop metabolic-engineered NAD+-Lac-OMVs nanovaccine with potent tissue repair therapeutic effect. NAD+-Lac-OMVs sequentially activate dendritic cells by membrane component and reprogram inflammatory macrophages for anti-inflammation and bone repair by interior nicotinamide metabolites.
Project description:Messenger RNA vaccines based on lipid nanoparticles (mRNA-LNPs) are promising vaccine modalities. However, mRNA-LNP vaccines frequently cause adverse reactions such as swelling and fever in humans, partly due to the inflammatory nature of LNP. Modification of the ionizable lipids used in LNP is one approach to avoid these adverse reactions. Herein, we report the development of mRNA-LNP vaccines with better protective immunity and reduced adverse reactions using LNP, including SS-cleavable and pH-activated lipid-like materials with oleic acid (ssPalmO) as an ionizable lipid (LNPssPalmO). We used mRNA expressing H5N1 subtype high-pathogenicity avian influenza virus-derived hemagglutinin or neuraminidase to generate mRNA-LNP vaccines against H5N1 influenza. Compared with conventional LNP, mRNA-LNPssPalmO induced comparable antigen-specific antibodies and better IFN--producing Th1 responses in mice. Both mRNA-LNPssPalmO and conventional mRNA-LNP conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared to conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPssPalmO induced less inflammatory responses (e.g., inflammatory cytokine production and vascular hyperpermeability) and fewer adverse reactions (e.g., weight loss and fever) compared with conventional mRNA-LNP. These results suggest that mRNA-LNPssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.
