Cells

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools—including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors—and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as PCSK9, ANGPTL3, CETP, APOC3, ASGR1, LPA, and IDOL, supported by findings from human genetics, preclinical models, and recent first-in-human trials. Emerging delivery vehicles (AAVs, LNPs, lentivirus, virus-like particles) and their translational implications are discussed. The review highlights ongoing clinical trials employing liver-targeted in vivo editing modalities (LivGETx-CVD) and provides insights into challenges in delivery, off-target effects, genotoxicity, and immunogenicity. Collectively, this review captures the rapid progress of LivGETx-CVD from conceptual innovation to clinical application, and positions gene editing as a transformative, single-dose strategy with the potential to redefine prevention and long-term management of dyslipidemia and atherosclerotic cardiovascular disease.

One group of human proteins found in the cytoplasm, but not in the nucleus, is characterized by the presence of short (6–9 aa), specific amino acid sequences thought to be involved in retaining proteins in the cytoplasm (cytoplasmic retention sequences). While strong evidence supports the ability of some peptides to act in this way, the number of such supported cases is small. We have taken the view that the situation would be improved by enhancing the methods available to identify cytoplasmic retention (CR) sequences. Here, we describe an appropriate bioinformatic method to identify CR peptides using information about their location at the ends of cytoplasmic proteins. The method was then used to link seven different human cytoplasmic proteins with sequences suggested to have cytoplasmic retention activity. Further bioinformatic analysis was carried out with isoforms of the cytoplasmic proteins identified. Amino acid sequence information showed that while the proposed CR amino acid sequences can be the same or distinct in different protein isoforms, they are always located at the same site in the protein. For instance, while the proposed retention sequence of CCDC57 isoform X18 is MLARLVSNS, in isoform 7 it is SEPALNEL, yet the two sequences are each located between amino acids 5 and 13 in the CCDC57 sequence. The results support the view that the protein isoform is involved in determining the location of the CR sequence in a protein, while the amino acid sequence itself affects other variables such as the sub-region of the cytoplasm the protein needs to occupy. Overall, the study yielded identification of 15 candidate CR peptides in which 10 of the 15 have unrelated amino acid sequences.

Alzheimer’s disease (AD) is increasingly recognized as a disorder that extends beyond amyloid-β (Aβ) and tau pathology. To this end, growing evidence suggests that aberrant neuronal cell cycle re-entry (CCR) may contribute to neurodegeneration. To investigate this mechanism, we profiled the expression of 84 cell cycle-related genes in the brains of aged APP/PS1 mice, a widely used transgenic model of AD, and compared them with age-matched non-transgenic littermates. Our analysis revealed 32 differentially expressed genes (DEGs), 8 of which exhibited significant changes (fold change > 2, p < 0.05). Several of these DEGs, including CDC7 and CCNC, displayed consistent dysregulation in human AD brains as assessed using the AMP-AD knowledge portal, supporting their translational relevance. Furthermore, integration with miRNA prediction analyses identified candidate post-transcriptional regulators of these DEGs, highlighting novel layers of regulation. Collectively, our results provide the first systematic overview of cell cycle gene dysregulation in aged APP/PS1 mice, establish cross-species concordance with human AD, and propose miRNA–gene interactions as potential contributors to neuronal vulnerability. These findings underscore the importance of cell cycle pathways in AD pathogenesis and point to new avenues for therapeutic exploration.