Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin.

Systemic diseases of liver origin (SDLO) are complex diseases in multiple organ systems, such as cardiovascular, musculoskeletal, endocrine, renal, respiratory, and sensory organ systems, caused by irregular liver metabolism and production of functional factors. Examples of such diseases discussed in this article include primary hyperoxaluria, familial hypercholesterolemia, acute hepatic porphyria, hereditary transthyretin amyloidosis, hemophilia, atherosclerotic cardiovascular diseases, α-1 antitrypsin deficiency-associated liver disease, and complement-mediated diseases. Nucleic acid therapeutics use nucleic acids and related compounds as therapeutic agents to alter gene expression for therapeutic purposes. The two most promising, fastest-growing classes of nucleic acid therapeutics are antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). For each listed SDLO disease, this article discusses epidemiology, symptoms, genetic causes, current treatment options, and advantages and disadvantages of nucleic acid therapeutics by either ASO or siRNA drugs approved or under development. Furthermore, challenges and future perspectives on adverse drug reactions and toxicity of ASO and siRNA drugs for the treatment of SDLO diseases are also discussed. In summary, this review article will highlight the clinical advantages of nucleic acid therapeutics in targeting the liver for the treatment of SDLO diseases. SIGNIFICANCE STATEMENT: Systemic diseases of liver origin (SDLO) contain rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO. This article aims to provide the most updated information on targeting the liver with antisense oligonucleotides and small interfering RNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of SDLO, which currently have no or limited options for treatment.

Health inequity in genomic personalized medicine in underrepresented populations: a look at the current evidence.

Improvements in sequencing technology coupled with dramatic declines in the cost of genome sequencing have led to a proportional growth in the size and number of genetic datasets since the release of the human genetic sequence by The Human Genome Project (HGP) international consortium. The HGP was undeniably a significant scientific success, a turning point in human genetics and the beginning of human genomics. This burst of genetic information has led to a greater understanding of disease pathology and the potential of employing this data to deliver more precise patient care. Hence, the recognition of high-penetrance disease-causing mutations which encode drivers of disease has made the management of most diseases more specific. Nonetheless, while genetic scores are becoming more extensively used, their application in the real world is expected to be limited due to the lack of diversity in the data used to construct them. Underrepresented populations, such as racial and ethnic minorities, low-income individuals, and those living in rural areas, often experience greater health disparities and worse health outcomes compared to the general population. These disparities are often the result of systemic barriers, such as poverty, discrimination, and limited access to healthcare. Addressing health inequity in underrepresented populations requires addressing the underlying social determinants of health and implementing policies and programs which promoted health equity and reduce disparities. This can include expanding access to affordable healthcare, addressing poverty and unemployment, and promoting policies that combat discrimination and racism.

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies.

Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

Climate change, human health, and the exposome: Utilizing OMIC technologies to navigate an era of uncertainty.

Climate change is an anthropogenic phenomenon that is alarming scientists and non-scientists alike. The emission of greenhouse gases is causing the temperature of the earth to rise and this increase is accompanied by a multitude of climate change-induced environmental exposures with potential health impacts. Tracking human exposure has been a major research interest of scientists worldwide. This has led to the development of exposome studies that examine internal and external individual exposures over their lifetime and correlate them to health. The monitoring of health has also benefited from significant technological advances in the field of "omics" technologies that analyze physiological changes on the nucleic acid, protein, and metabolism levels, among others. In this review, we discuss various climate change-induced environmental exposures and their potential health implications. We also highlight the potential integration of the technological advancements in the fields of exposome tracking, climate monitoring, and omics technologies shedding light on important questions that need to be answered.

Effects of Metformin Combined With Antifolates on HepG2 Cell Metabolism and Cellular Proliferation.

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Furthermore, a growing body of evidence shows that cancer metabolic changes are a key feature of many types of human malignancies. Metabolic reprogramming refers to cancer cells' ability to change their metabolism in order to meet the increased energy demand caused by continuous growth, rapid proliferation, and other neoplastic cell characteristics. For these reasons, metabolic pathways may become new therapeutic and chemopreventive targets. The aim of this study was to investigate the metabolic alterations associated with metformin (MET), an anti-diabetic agent when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate (MTX), and how metabolic changes within the cancer cell may be used to increase cellular death. In this study, single drugs and combinations were investigated using in vitro assays including cytotoxicity assay (MTT), RT-qPCR, annexin V/PI apoptosis assay, scratch wound assay and Seahorse XF analysis, on a human HCC cell line, HepG2. The cytotoxicity assay showed that the IC50 of MET as single therapy was 44.08 mM that was reduced to 22.73 mM and 29.29 mM when combined with TMP and MTX, respectively. The co-treatment of both drugs increased p53 and Bax apoptotic markers, while decreased the anti-apoptotic marker; Bcl-2. Both combinations increased the percentage of apoptotic cells and halted cancer cell migration when compared to MET alone. Furthermore, both combinations decreased the MET-induced increase in glycolysis, while also inducing mitochondrial damage, altering cancer cell bioenergetics. These findings provide an exciting insight into the anti-proliferative and apoptotic effects of MET and anti-folates on HepG2 cells, and how in combination, may potentially combat the aggressiveness of HCC.