Lipid-lowering drugs, especially statins, are extensively utilized in clinical settings for the prevention of hyperlipidemia. Nevertheless, prolonged usage of current lipid-lowering medications is associated with significant adverse reactions. Therefore, it is imperative to develop novel therapeutic agents for lipid-lowering therapy. In this study, a chenodeoxycholic acid and lactobionic acid double-modified polyethyleneimine (PDL) nanocomposite as a gene delivery vehicle for lipid-lowering therapy by targeting the liver, are synthesized. Results from the in vitro experiments demonstrate that PDL exhibits superior transfection efficiency compared to polyethyleneimine in alpha mouse liver 12 (AML12) cells and effectively carries plasmids. Moreover, PDL can be internalized by AML12 cells and rapidly escape lysosomal entrapment. Intravenous administration of cyanine5.5 (Cy5.5)-conjugated PDL nanocomposites reveals their preferential accumulation in the liver compared to polyethyleneimine counterparts. Systemic delivery of low-density lipoprotein receptor plasmid-loaded PDL nanocomposites into mice leads to reduced levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TC) in the bloodstream without any observed adverse effects on mouse health or well-being. Collectively, these findings suggest that low-density lipoprotein receptor plasmid-loaded PDL nanocomposites hold promise as potential therapeutics for lipid-lowering therapy.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

Improving target versus off-target ratio in nanomedicine remains a major challenge for increasing drug bioavailability and reducing toxicity. Active targeting using ligands on nanoparticle surfaces is a key approach but has limited clinical success. A potential issue is the integration of targeting ligands also changes the physicochemical properties of nanoparticles (passive targeting). Direct studies to understand the mechanisms of active targeting and off-targeting in vivo are limited by the lack of suitable tools. Here, the biodistribution of a representative active targeting liposome is analyzed, modified with an apolipoprotein E (ApoE) peptide that binds to the low-density lipoprotein receptor (LDLR), using zebrafish embryos. The ApoE liposomes demonstrated the expected liver targeting effect but also accumulated in the kidney glomerulus. The ldlra-/- zebrafish is developed to explore the LDLR-specificity of ApoE liposomes. Interestingly, liver targeting depends on the LDLR-specific interaction, while glomerular accumulation is independent of LDLR and peptide sequence. It is found that cationic charges of peptides and the size of liposomes govern glomerular targeting. Increasing the size of ApoE liposomes can avoid this off-targeting. Taken together, the study shows the potential of the zebrafish embryo model for understanding active and passive targeting mechanisms, that can be used to optimize the design of nanoparticles.

UNASSIGNED: A certain level of low-density lipoprotein receptor activity is crucial for the efficacy of PCSK9i. Therapeutic strategies for familial hypercholesterolemia patients should consider drug efficacy, and genetic testing will be helpful.
UNASSIGNED: Familial hypercholesterolemia (FH) is a serious autosomal dominant disorder. Managing blood lipids in FH patients poses greater challenges for clinicians. Drug therapy may not always yield satisfactory results, particularly in individuals with low-density lipoprotein receptor (LDLR) negative mutations. Herein, we report a young female harboring an LDLR frameshift mutation. This patient developed xanthomas at 7 months old and underwent several years of treatment involving four classes of lipid-lowering drugs, including PCSK9i. However, the response to drug therapy was limited in this patient and eventually culminated in premature myocardial infarction. The efficacy of PCSK9i depends on the activity of LDLR. The inefficacy of PCSK9i may arise from the extensive mutations which leading to loss of LDLR activity. Therapy plans for these patients should take into account the efficacy of drug therapy. Early genetic testing is crucial for clinicians to make informed decisions regarding therapy options.

Although benign, ameloblastoma is a locally aggressive lesion in some patients and the development of additional treatments is needed. Verteporfin (VP) is a photosensitizer exhibiting considerable photocytotoxicity in various tumor cells. We aimed to investigate the effects of verteporfin photodynamic therapy (VP PDT) on ameloblastoma.
Eighteen patients who underwent surgery for ameloblastoma were randomly selected. We performed an immunohistochemical assessment to investigate the expression of low-density lipoprotein receptor (LDLR) and Yes-associated protein (YAP), targets of VP, in human ameloblastoma tissues and cultured human ameloblastoma cell line (HAM1). The effect of VP PDT on cell proliferation and apoptosis in HAM1 was analyzed.
The expression of LDLR and YAP were detected in human ameloblastoma tissues and HAM1. LDLR expression was significantly higher in patients who had previously undergone surgery than in patients who were receiving it for the first time. The cytotoxic effect of the combination of low-concentration VP administration and laser irradiation was comparable to high-concentration VP administration with and without laser irradiation. The addition of laser irradiation to VP administration significantly accelerated apoptotic bleb formation compared with VP administration alone.
VP PDT has the potential to become an additional treatment for large-sized ameloblastoma.

Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension (PH). However, the role of low-density lipoprotein receptor (LDL-R) in PH is not known. Methods and Results We examined the role of LDL-R in the development of PH and determined the efficacy of high-density lipoprotein mimetic peptide 4F in mitigating PH. Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL-R null (LDL-R knockout) mice (12-15 months old) were fed chow, Western diet (WD), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real-time quantitative reverse transcription-polymerase chain reaction, and histological analysis were performed. The effect of LDL-R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL-R and CD36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL, E06 immunoreactivity, and plasma oxidized LDL/LDL ratio. LDL-R knockout mice on WD developed PH, right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL-R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL-R in lungs and increased oxidized LDL in lungs and plasma. WD-fed LDL-R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL-R and oxidized lipids in PH.