RT Journal Article SR Electronic T1 Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin JF Pharmacological Reviews JO Pharmacol Rev FD American Society for Pharmacology and Experimental Therapeutics SP PHARMREV-AR-2022-000815 DO 10.1124/pharmrev.123.000815 A1 Anagha Gogate A1 Jordyn Belcourt A1 Milan Shah A1 Alicia Zongxun Wang A1 Alexis Frankel A1 Holly Kolmel A1 Matthew Chalon A1 Prajith Stephen A1 Aarush Kolli A1 Sherouk M Tawfik A1 Jing Jin A1 Raman Bahal A1 Theodore P Rasmussen A1 Jose E Manautou A1 Xiao-bo Zhong YR 2023 UL http://pharmrev.aspetjournals.org/content/early/2023/09/11/pharmrev.123.000815.abstract AB 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, alpha-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 SDLO diseases contain both rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO diseases. This article aims to provide the most updated information on targeting the liver with ASO and siRNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of some human systemic diseases, which currently have no or limited options for treatment.