Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.

Severe hemophilia is associated with spontaneous, prolonged and recurrent bleeding. Inadequate prevention and treatment of bleeding can lead to serious morbidity and mortality. Due to the limitations of intravenous clotting factor replacement, including the risk of inhibitory antibodies, innovative novel therapies have been developed that have dramatically changed the landscape of hemophilia therapy. Ribonucleic acid interference (RNAi) has brought the opportunity for multiple strategies to manipulate the hemostatic system and ameliorate the bleeding phenotype in severe bleeding disorders. Fitusiran is a RNAi therapeutic that inhibits the expression of the natural anticoagulant serpin antithrombin. Reduction in antithrombin is known to cause thrombosis if coagulation parameters are otherwise normal and can rebalance hemostasis in severe hemophilia. Reports from late stage clinical trials of fitusiran in hemophilia A and B participants, with and without inhibitory antibodies to exogenous clotting factor, have demonstrated efficacy in preventing bleeding events showing promise for a future \"universal\" prophylactic treatment of individuals with moderate-severe hemophilia.

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Increased CCKBR expression density or frequency has been reported in many neoplasms.
We aimed to investigate whether CCKBR drives the growth of gastric cancer (GC) and its potential as a therapeutic target of immunotoxins.
A lentiviral interference system was used to generate CCKBR-knockdown gastric cancer cells. Cell Counting Kit-8 and clonogenic assays were used to evaluate cell proliferation. Woundhealing and cell invasion assays were performed to evaluate cell mobility. Cell cycle was analyzed by flow cytometry. Tumor growth in vivo was investigated using a heterologous tumor transplantation model in nude mice. In addition, we generated the immunotoxin FQ17P and evaluated the combining capacity and tumor cytotoxicity of FQ17P in vitro.
Stable downregulation of CCKBR expression resulted in reduced proliferation, migration and invasion of BGC-823 and SGC-7901 cells. The impact of CCKBR on gastric cancer cells was further verified through CCKBR overexpression studies. Downregulation of CCKBR expression also inhibited the growth of gastric tumors in vivo. Furthermore, FQ17P killed CCKBR-overexpressing GC cells by specifically binding to CCKBR on the tumor cell surface.
The CCKBR protein drives the growth, migration, and invasion of gastric cancer cells, and it might be a promising target for immunotoxin therapy based on its aberrant expression, functional binding interactions with gastrin, and subsequent internalization.

[This corrects the article DOI: 10.3389/fpls.2020.00069.].

Verticillium wilt caused by Verticillium dahliae is a destructive cotton disease causing severe yield and quality losses worldwide. WRKY transcription factors play important roles in plant defense against pathogen infection. However, little has been reported on the functions of WRKYs in cotton\'s resistance to V. dahliae. Here, we identified 5, 5, and 10 WRKY70 genes in Gossypium arboreum, Gossypium raimondii, and Gossypium hirsutum, respectively, and investigated the expression profiles of all GhWRKY70 genes in various cotton tissues and in response to hormone treatment or V. dahliae infection. Reverse transcription-quantitative PCR analysis showed that GhWRKY70D13 was expressed higher in roots and stems than in other tissues, and up-regulated after V. dahliae inoculation. Knock-down of GhWRKY70D13 improved resistance to V. dahliae in both resistant and susceptible cotton cultivars. Comparative analysis of transcriptomes generated from wild-type and stable RNAi (RNA interference) plant with down-regulated GhWRKY70D13 showed that genes involved in ethylene (ET) and jasmonic acid (JA) biosynthesis and signaling were significantly upregulated in the GhWRKY70D13 RNAi plants. Consistently, the contents of 1-aminocyclopropane-1-carboxylic (ACC), JA, and JA-isoleucine levels were significantly higher in the GhWRKY70D13 RNAi plants than in wild-type. Following V. dahliae infection, the levels of ACC and JA decreased in the GhWRKY70D13 RNAi plants but still significantly higher (for ACC) than that in wild-type or at the same level (for JA) as in non-infected wild-type plants. Collectively, our results suggested that GhWRKY70D13 negatively regulates cotton\'s resistance to V. dahliae mainly through its effect on ET and JA biosynthesis and signaling pathways.

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms \'inotersen,\' \'AG10,\' \'antisense oligonucleotide,\' \'hereditary transthyretin amyloidosis,\' \'familial amyloid polyneuropathy,\' and \'familial amyloid cardiomyopathy\' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia.

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis is caused by a mutation in transthyretin (TTR) gene resulting in misfolded TTR protein accumulating as amyloid fibrils. Patisiran is a lipid nanoparticle formulation of ribonucleic acid interference (RNAi), which can reduce the production of TTR. Areas covered: In this review, the chemical property, mechanism of action, pharmacokinetics, clinical efficacy, and safety of patisiran were introduced. Expert Commentary: Patisiran offers a new treatment option for patients with hereditary transthyretin-mediated amyloidosis. Patisiran can significantly reduce the TTR level and improve patient\'s neuropathy and quality of life. The common adverse reactions were upper respiratory tract infections and infusion-related reactions.

BACKGROUND: Glaucoma is a collection of optic neuropathies consisting of retinal ganglion cell death and corresponding visual field loss. Glaucoma is the leading cause of irreversible vision loss worldwide and is forecasted to precipitously increase in prevalence in the coming decades. Current treatment options aim to lower intraocular pressure (IOP) via topical or oral therapy, laser treatment to the trabecular meshwork or ciliary body, and incisional surgery. Despite increasing use of trabecular laser therapy, topical therapy remains first-line in the treatment of most forms of glaucoma. Areas covered: Novel glaucoma therapies are a long-standing focus of investigational study. More than two decades have passed since the last United States Food and Drug Administration (FDA) approval of a topical glaucoma drug. Here, the authors review established topical glaucoma drops as well as those currently in FDA phase 2 and 3 clinical trial, nearing clinical use. Expert opinion: Current investigational glaucoma drugs lower IOP, mainly through enhanced trabecular meshwork outflow. Although few emerging therapies show evidence of retinal ganglion cell and optic nerve neuroprotection in animal models, emerging drugs are focused on lowering IOP, similar to established medicines.