Molecular Therapy

Long noncoding RNAs (lncRNAs) are a distinct subtype of RNA that lack protein-coding capacity but exert significant influence on various cellular processes. In non-small cell lung cancer (NSCLC), dysregulated lncRNAs act as either oncogenes or tumor suppressors, contributing to tumorigenesis and tumor progression. LncRNAs directly modulate gene expression, act as competitive endogenous RNAs (ceRNAs) by interacting with microRNAs or proteins, and associate with RNA binding proteins (RBPs). Moreover, lncRNAs can reshape tumor immune microenvironment, influence cellular metabolism, cancer cell stemness, and angiogenesis by engaging various signaling pathways...

In recent years, there has been a surge in the innovative modification and application of the viral vector-based gene therapy field. Significant and consistent improvements in the engineering, delivery and safety of viral vectors have set the stage for their application as RNAi delivery tools. Viral vector-based delivery of RNAi has made remarkable breakthroughs in the treatment of several debilitating diseases and disorders (e.g., neurological diseases); however, their novelty has yet to be fully applied and utilized for the treatment of cancer...

Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2 positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer- associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC...

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m6 A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (Log rank test, p<0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m6 A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo...

Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of Th17 cells, germinal center B cells and plasma cells...

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodelling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. Polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility and severity of asthma. We investigated the efficacy of human MSCs in high vs low hMIF environments and the impact of MIF pre-licensing of MSCs using humanised MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma...

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No abstract text is available yet for this article.

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Chimeric antigen receptor (CAR)-T cells represent a promising frontier in cancer immunotherapy. However, the current process for developing new CAR constructs is time-consuming and inefficient. To address this challenge and expedite the evaluation and comparison of full-length CAR designs, we have devised a novel cloning strategy. This strategy involves the sequential assembly of individual CAR domains using blunt ligation, with each domain being assigned a unique DNA barcode. Applying this method, we successfully generated 360 CAR constructs that specifically target clinically validated tumor antigens CD19 and GD2...

Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed a myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy...

The ongoing evolution of SARS-CoV-2, resulting in the emergence of new variants that are resistant to existing vaccines and therapeutic antibodies, has raised the need for novel strategies to combat the persistent global COVID-19 epidemic. In this study, a monoclonal anti-human angiotensin-converting enzyme 2 (hACE2) antibody, ch2H2, was isolated and humanized to block the viral receptor-binding domain (RBD) binding to hACE2, the major entry receptor of SARS-CoV-2. This antibody targets the RBD binding site on the N-terminus of hACE2 and has a high binding affinity to outcompete the RBD...

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin to mimic human FSGS...

In vivo CRISPR gene therapy holds large clinical potential, but the safety and efficacy remain largely unknown. Here, we injected a single dose of HSV-1-targeting CRISPR formulation in the cornea of three patients with severe refractory herpes stromal keratitis (HSK) during corneal transplantation. Our study is an investigated initiated, open-label, single-arm, non-randomized interventional trial at a single center (NCT04560790). We found neither detectable CRISPR-induced off-target cleavages by GUIDE-seq nor systemic adverse events for 18 months on average in all three patients...

Genome-wide association studies indicate that allele variants in MIR137, the host gene of microRNA-137 (miR137), confer an increased risk of schizophrenia (SCZ). Aberrant expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. Thus, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA...

A deficiency of human arylsulfatase A (hASA) causes metachromatic leukodystrophy (MLD), a lysosomal storage disease characterized by sulfatide accumulation and CNS demyelination. Efficacy of enzyme replacement therapy (ERT) is increased by genetic engineering of hASA to elevate its activity and transfer across the blood-brain barrier (BBB), respectively. To further improve the enzyme's bioavailability in the CNS, we mutated a cathepsin cleavage hot spot and obtained hASAs with substantially increased half-lives...

The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28- effector CD8 T cells, of CCR7- CD45RO+ effector memory and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory T cells present gene, protein and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4β1 integrin...

Fibroblast activation protein (FAP) is a cell surface serine protease that is highly expressed on reactive stromal fibroblasts, such as cancer-associated fibroblasts (CAFs), and generally absent in healthy adult tissues. FAP expression in the tumor stroma has been detected in more than 90% of all carcinomas, rendering CAFs excellent target cells for a tumor site-specific adenoviral delivery of cancer therapeutics. Here, we present a tropism-modified human adenovirus 5 (Ad5) vector that targets FAP through trivalent, designed ankyrin repeat protein (DARPin)-based retargeting adapters...

Pirfenidone and nintedanib are only anti-pulmonary fibrosis (PF) drugs approved by FDA. However, they are not target-specific, and unable to modify the disease status. Therefore, it is still desirable to discover more effective agents against PF. Vimentin (VIM) plays key roles in tissue regeneration and wound healing, but its molecular mechanism remains unknown. In this work, we demonstrated that atractylodinol (ATD) significantly inhibits TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT) in vitro...