The transcription factor BTB and CNC homology 1 (BACH1) is linked to coronary artery disease risk and impairs angiogenesis after ischemic injury. However, there is a scarcity of specific BACH1 inhibitors. This study identifies BI033 as a selective BACH1 inhibitor, confirming its binding to the 91st alanine in BACH1's N-terminal. BI033 shows lower toxicity in human umbilical vein endothelial cells (HUVECs)

Cytokines are promising in cancer immunotherapy, but their pleiotropic effects limit specificity and clinical utility. Through binding to IL-18Rα and IL-18Rβ, interleukin-18 (IL-18) stimulates innate lymphocytes and effector T cells for antitumor immunity. However, clinical trials of recombinant IL-18 have been hampered by IL-18 binding protein (IL-18BP), a secreted high-affinity decoy receptor. Here

A significant limitation of hematopoietic stem cell transplantation (HSCT) that reduces its application across more disease areas and more geographically diverse populations is the toxicity from chemotherapy-based conditioning. A potential solution is to replace chemotherapy with monoclonal antibodies, but the replacement must result in therapeutically relevant levels of engraftment. In some cases

CAR T cell therapy has proven remarkably successful for the treatment of haematological malignancies. However, the bespoke manufacturing of autologous CAR T cells is complex and expensive. The development of methods for in vivo engineering of T cells will enable generation of CAR T cells directly within the patient, bypassing the need for ex vivo manufacturing thereby enabling greater access for patients

An emerging technique for the treatment of type 1 diabetes, which is characterized by hyperglycemia resulting from the loss of insulin-secreting β cells, involves transplantation of human pluripotent stem cell (hPSC)-derived β cells. This transplantation procedure can induce normoglycemia, yet the efficiency of cell survival and function post transplantation remain opportunities for improvement. Here

Duchenne muscular dystrophy (DMD) is the most common childhood-onset muscle degenerative disease, caused by genetic deficiency of dystrophin, resulting in premature death due to cardiorespiratory failure. Gene therapy clinical trials employing adeno-associated virus (AAV) systemically delivering miniaturized dystrophin have provided mixed results with lingering concerns about safety, long-term efficacy

Personalized treatment has become a realistic option for tumor patients, accelerated by significantly reduced sequencing costs of tumor genomes and advances in vaccine formulations. The druggability of cancer neo-antigens caused by individual mutations is centered in this effort. We here use an AAV-based VLP platform to compose a neo-antigen specific protein vaccine that is effective in a murine prevention

Colorectal cancer, characterized by its aggressive metastatic behavior and often poor prognosis, urgently necessitates improved diagnostic and therapeutic strategies. This study introduces HY-4, an aptamer developed via a non-SELEX method, which shows exceptional specificity and affinity for nucleolin (NCL), a highly expressed oncogenic protein in various cancers. With remarkable biocompatibility,

The CRISPR-Cas9 system is rewriting the treatment of genetic diseases, offering unprecedented potential for detrimental and previously untreatable diseases. As this technology advances toward wider utilization in clinical applications, the immunogenicity of Cas9 nuclease has emerged as a potential challenge for in vivo therapies. Immune recognition of CRISPR-Cas9 components can trigger both innate

We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness. The phase 1b/2a trial (NCT05616793) is a nonrandomized, single ascending, dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26, and 34 years old) received uniocular subretinal

Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the Food and Drug Administration-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated

Epidermal growth factor receptor (EGFR) plays a crucial role in cellular processes such as development and tissue repair, with dysregulation linked to various diseases, including those affecting energy metabolism. Previous studies have reported that EGFR ligands enhance glucose homeostasis through various mechanisms across different tissues. However, epigen, the latest EGFR ligand, has not been thoroughly

Severe alcohol-associated hepatitis (SAH) is a life-threatening condition with high mortality rates and poor response to prednisolone therapy. Identifying reliable early predictors of therapy response and survival is critical. Plasma metabolomics was conducted on 70 SAH patients (50 responders and 20 non-responders) to identify biomarkers for non-response and early mortality. These findings were validated

Galectin-4 (Gal-4), a member of the β-galactoside-binding galectin family, plays a role in various physiological processes, including tumor progression and intestinal disorders. However, its contribution to adaptive immunity remains poorly understood. In this study, Gal-4 is identified as a critical factor for effective generation of CD8+ T cell responses against tumors and viral infections. Gal-4-deficient

In this case series, we report the first off-label use of the CD19xCD3 T cell engager blinatumomab in two patients with generalized myasthenia gravis (MG). Refractory MG remains a major therapeutic challenge, with patients experiencing severe disability and potentially life-threatening crises despite intensive immunotherapy. This study evaluates the clinical efficacy and safety of short-term blinatumomab

Sudden sensorineural hearing loss (SSNHL) is a prevalent condition in otolaryngology with poorly understood mechanisms. Inner ear labyrinthine hemorrhage (IELH) is a potentially significant cause. Our study focused on the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation following IELH and the protective role of the NLRP3 inhibitor CY-09. In mice with IELH, significant increases

In vitro-transcribed (IVT) mRNA therapeutics are promising for preventing and treating diseases, including infectious diseases and cancer, by delivering nucleic acid sequences. Assessing the stability of mRNA sequences and poly(A) tail length is crucial to minimize adverse effects and ensure drug efficacy. However, accurately measuring long homopolymeric nucleotides remains technically challenging

Thrombotic microangiopathy (TMA) has been reported as an uncommon but severe adverse effect of recombinant adeno-associated virus (rAAV)-based gene therapy. Here, we describe in detail the occurrences of clinically evident TMA following infusion of the rAAV9-based therapy fordadistrogene movaparvovec (1 or 3 × 1014 vg/kg) in 22 participants with Duchenne muscular dystrophy (DMD). Three participants

Fordadistrogene movaparvovec (FM; PF-06939926) is a recombinant adeno-associated virus serotype-9 gene-replacement construct containing a mini-dystrophin transgene in development for Duchenne muscular dystrophy (DMD). We present findings of cardiac safety assessments in participants with DMD during a 1-year follow-up from an ongoing phase 1b multicenter, single-arm, open-label trial of low- and high-dose

Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor, CD146, in proximal tubules, with higher expression in patients

The epigenetic landscape governs cell fate decisions during development, aging, and disease. Despite considerable progress in the understanding of DNA methylation (DNAm), the mechanisms that orchestrate its coordinated regulation across the genome remain largely elusive. Recent breakthroughs in sequencing technologies and epigenetic editing tools enable a more comprehensive exploration of these epigenetic

The development of chimeric antigen receptor (CAR) T cell therapies has greatly impacted the treatment of B cell malignancies; however, manufacturing these patient-specific, autologous cell therapies is complex, costly, and requires preconditioning chemotherapy prior to infusion, limiting patient access. Here we describe the development of a lentiviral platform based on a novel, detargeted viral fusogen

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease affecting the neuromuscular junction. Refractory MG, particularly in cases associated with rare anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, presents significant treatment challenges. Teclistamab, a bispecific antibody targeting B cell maturation antigen (BCMA) and CD3, redirects T cells against plasma cells

Cystic fibrosis (CF) is a severe genetic disorder caused by loss-of-function mutations in the CFTR gene. Gene-editing approaches have the potential to correct such mutations. This systematic review outlines the mechanisms of the main CRISPR-based technologies, and, through cross-study comparisons, analyzes 27 research articles that applied them to target CF-causing variants. We report and discuss the

Over 300 million people worldwide suffer from chronic hepatitis B virus (HBV) infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic

Absence of functional acid-α-glucosidase (GAA) leads to early onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa−/−) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline)

Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against

Transactive response DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891

Covalently closed-end adeno-associated virus (cceAAV) vector is a new generation of self-complementary adeno-associated virus (scAAV) vector that does not utilize a mutant inverted terminal repeat (ITR) for vector production. Importantly, packaged genomes of these cceAAV vectors are markedly more intact than traditional scAAVs, which typically contain a large fraction of incomplete genomes, including

Hutchinson-Gilford progeria syndrome (HGPS), an extremely rare progressive genetic disorder, is caused by a point mutation in LMNA that induces progerin production, which disrupts cellular function and triggers premature aging and mortality. Despite extensive efforts, HPGS remains incurable. We successfully implemented a strategy using RfxCas13d to selectively target progerin mRNA at specific junction

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder involving ventricular arrhythmias, cardiac dysfunction, and fibrofatty myocardial replacement. Current treatments are largely palliative, with heart transplantation as the only definitive option for advanced ACM. Here, we show that, building upon our previous identification of a patient with a PNPLA2c.G245A/c.G245A mutation, we developed

Adenine base editors (ABEs) and cytosine base editors (CBEs) are prominent tools for precise genome editing but are hindered by limited editing activity at positions proximal to the protospacer adjacent motif (PAM). This study investigates the potential of enhancing base editors editing activity by fusing them with RNA-DNA hybrid binding domains (RHBDs). Specifically, fusing ABE8e with the RHBD of

Phenylketonuria (PKU) is a genetic defect caused by lack of the liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood phenylalanine (Phe) levels and neurotoxicity, which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe

Epilepsy affects approximately 50 million people worldwide, and over 30% of patients are considered treatment resistant to currently available anti-seizure drugs. Neuropeptide Y (NPY) has been shown to inhibit excitatory synaptic transmission in hippocampal slices from human epilepsy patients via Y2 receptors (Y2Rs), and overexpression of NPY and/or Y2R in the hippocampus reduces seizures in rodent

Glycoengineering of IgG, particularly Fc glycosylation, holds significant promise for treating autoimmune diseases by modulating antibody effector functions. However, methods that precisely control IgG glycosylation profiles in vivo are still lacking. In this study, by delivering mRNAs encoding the glycosyltransferases B4GALT1 and ST6GAL1 intravenously, we successfully expressed functional enzymes

Adenosine-to-inosine (A-to-I) RNA editing, and N6 methyladenosine (m6A) are among the most abundant modifications in eukaryotic messenger RNA, affecting various aspects of RNA metabolism and cellular function, including proliferation, differentiation, responses to stressors, and cell death. Recent preclinical evidence suggests that both modifications play a significant role in multiple disorders, including

Natural killer cells are innate lymphocytes equipped with the ability to rapidly identify and eliminate cancer cells. However, cancer cells release nanosized extracellular vesicles that can induce an immunosuppressive tumor microenvironment, subsequently hindering natural killer cell immunosurveillance. Studies have reported that extracellular vesicles derived from different cancers, such as acute

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal malignancies, highlighting the critical need for innovative therapeutic strategies. In this study, we examined the roles of nicotinamide adenine dinucleotide (NAD) synthesis pathway in PDAC. Targeting the NAD synthesis pathway significantly mitigated lethality in a Drosophila model that recapitulated the PDAC genotype. Within this

Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a monogenic disorder caused by mutations in the ADA gene. Gene therapy using γ-retroviral and lentiviral vector gene addition approaches have shown curative results. We sequenced the ADA transgene in transduced CD3+ T cells, and in peripheral blood cells from patients treated with autologous CD34+ cells transduced with either a γ-retroviral

T cell receptor (TCR)-engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen-heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac).

Podocyte injury contributes to the progression of glomerular disease and aging; however, causative molecular/physiological pathways are poorly defined, and there are few therapies to improve kidney outcomes. We previously reported that free fatty acid receptor 4 (FFAR4) agonist TUG891 improved podocyte injury to alleviate renal inflammation and fibrosis in diabetic nephropathy. However, the role of