Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut
Pharmacol Rev. 2023 Dec 15;76(1):49-89. doi: 10.1124/pharmrev.123.000815.
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, -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.
肝脏起源的系统性疾病 (SDLO) 是多种器官系统的复杂疾病，如心血管、肌肉骨骼、内分泌、肾脏、呼吸和感觉器官系统，由肝脏代谢和功能因子产生的不规则引起。本文讨论的此类疾病包括原发性高草酸尿症、家族性高胆固醇血症、急性肝卟啉症、遗传性转甲状腺素淀粉样变性、血友病、动脉粥样硬化性心血管疾病、-1 抗胰蛋白酶缺乏相关肝病和补体介导的疾病。核酸疗法使用核酸和相关化合物作为治疗剂，通过改变基因表达来达到治疗目的。最有前途、发展最快的两类核酸疗法是反义寡核苷酸 (ASO) 和小干扰 RNA (siRNA)。对于列出的每种 SDLO 疾病，本文讨论了流行病学、症状、遗传原因、当前治疗选择以及已批准或正在开发的 ASO 或 siRNA 药物的核酸疗法的优缺点。此外，还讨论了 ASO 和 siRNA 药物治疗 SDLO 疾病时的药物不良反应和毒性的挑战和未来展望。总之，本文综述将强调核酸疗法靶向肝脏治疗 SDLO 疾病的临床优势。意义陈述：肝脏起源的系统性疾病 (SDLO) 包含由肝脏功能异常引起的罕见和常见的复杂疾病。核酸疗法已显示出治疗 SDLO 的有前途的临床优势。本文旨在提供使用反义寡核苷酸和小干扰 RNA 药物靶向肝脏的最新信息。所产生的知识可能会激发对这一不断发展的新治疗实体领域的进一步研究，目前这些治疗实体对 SDLO 的治疗方法有限或没有。
