Molecular Therapy最新文献

Effective treatment strategies to alleviate heart failure that develops as a consequence of myocardial infarction (MI) remain an unmet need in cardiovascular medicine. In this study, we uncover that exosomes produced by human Tohoku Hospital Pediatrics-1 (THP-1) macrophages cultured with the cytokine interleukin-4 (THP1-IL4-exo) reverse cardiac functional decline in mice that developed MI in response to diet-induced occlusive coronary atherosclerosis. The therapeutic benefits of THP1-IL4-exo stem from their ability to drive transcriptional reprogramming of inflammatory responses in myeloid cells. Notably, repeated infusions of THP1-IL4-exo led to the suppression of type 1 interferon signaling in circulating Ly-6C^hi monocytes as well as in myeloid cells within the bone marrow and cardiac tissue. In vitro studies with primary macrophages stimulated with double-stranded DNA confirmed an ability for THP1-IL4-exo to confer suppression of type 1 interferon-mediated immune activation and inflammation. Collectively, these benefits contribute to the control of myelopoiesis, recruitment of cardiac myeloid cells, and preservation of populations of resident cardiac macrophages that together mitigate cardiac inflammation, adverse ventricular remodeling, and heart failure. Our findings introduce THP1-IL4-exo, one form of M2-macrophage exosomes, as novel anti-inflammatory and tissue repair therapeutics to preserve cardiac function post-MI.

Targeted antigen delivery to immune cells, particularly dendritic cells, has emerged as a promising strategy to enhance therapeutic efficacy of vaccines, while minimizing adverse effects associated with conventional immunization. In this study, we use our previously described small glycomimetic molecule that is selectively recognized by the Langerhans cell (LC)-specific surface receptor Langerin and demonstrate specific delivery of protein antigens to these specialized dendritic cells. Our results show that Langerin-mediated antigen delivery significantly enhances the immune response in vivo, resulting in increased expansion and activation of antigen-specific T cells, compared to immunization with unmodified antigen. We demonstrate the feasibility of our LC-targeted platform for immune cell-specific immunization with protein antigen and underscore the potential of LCs as an access point for next-generation vaccines and immunotherapies.

Hemophilia B gene therapy treatments have not addressed the need for predictable, durable, active, and redosable factor IX (FIX). Unlike conventional gene therapy, engineered B cell medicines (BCMs) are durable, redosable, and titratable and thus have the potential to address significant unmet needs in the hemophilia B treatment paradigm. BE-101 is an autologous BCM comprising expanded and differentiated B lymphocyte lineage cells genetically engineered ex vivo to secrete factor IX (FIX)-Padua. CRISPR-Cas9-mediated gene editing at the C-C chemokine receptor type 5 (CCR5) locus was used to facilitate transgene insertion of an adeno-associated virus 6-encoded DNA template via homology-directed repair. Transgene insertion did not alter B cell biology, viability, or differentiation into plasma cells. Appreciable levels of BE-101-derived FIX-Padua were detected within 1 day after IV administration in mice, and steady state was reached within 2 weeks and persisted for over 184 days. Redosing produced an increase in FIX-Padua production close to linear dose proportionality. Comprehensive genotoxicity analysis found no off-target issues of concern. No safety signals were observed in animal tolerability and Good Laboratory Practice toxicology studies. In conclusion, BE-101 produces sustained levels of active FIX-Padua with the ability to engraft without host preconditioning and with the potential for redosing and titratability.

Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE) and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single adeno-associated virus, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference (RNAi)-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting only Hif1a in photoreceptors or Hif2a in the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.

Epigenome editing is emerging as a transformative approach in clinical treatment, enabling precise modifications to gene expression without altering the underlying DNA sequence. The ongoing transition of epigenome editing techniques from foundational research to clinical applications highlights several key strategies. These include targeted DNA methylation/demethylation, histone modification, and transcriptional regulation. These approaches offer the potential for durable and reversible gene expression modulation, paving the way for precisely tailored therapies for genetic and complex diseases. Here, we review pioneering research, technological advancements, granted patents, and clinical trials that have been reported during the past decade. By synthesizing current research and development efforts, this review aims to provide insights into the promising landscape of epigenome editing and its potential to promote therapeutic interventions.

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor for developing glaucoma, induced mitochondrial fragmentation in retinal capillary ECs, accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant-negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.