Department of Nephrology, Rambam Healthcare Campus, Haifa, Israel.
Departments of Genetics and Developmental Biology and Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
Curr Opin Nephrol Hypertens. 2024 Jul 1;33(4):447-455. doi: 10.1097/MNH.0000000000000977. Epub 2024 Feb 28.
More than a decade ago, apolipoprotein L1 ( APOL1 ) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased risk for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending to the development and clinical testing of genomically precise small molecule therapy accompanied by emergence of RNA medicine platforms and clinical testing within just over a decade.
Given the plethora of excellent prior review articles, we will focus on new findings regarding unresolved questions relating mechanism of cell injury with mode of inheritance, regulation and modulation of APOL1 activity, modifiers and triggers for APOL1 kidney risk penetrance, the pleiotropic spectrum of APOL1 related disease beyond the kidney - all within the context of relevance to therapeutic advances.
Notwithstanding remaining controversies and uncertainties, promising genomically precise therapies targeted at APOL1 mRNA using antisense oligonucleotides (ASO), inhibitors of APOL1 expression, and small molecules that specifically bind and inhibit APOL1 cation flux are emerging, many already at the clinical trial stage. These therapies hold great promise for mitigating APOL1 kidney injury and possibly other systemic phenotypes as well. A challenge will be to develop guidelines for appropriate use in susceptible individuals who will derive the greatest benefit.
综述目的：十多年前，载脂蛋白 L1（APOL1）风险等位基因 G1 和 G2 被发现与近期非洲裔个体进行性肾脏疾病风险显著增加有关。在这期间取得了令人欣慰的进展，包括开发和临床测试基因组精确的小分子治疗方法，以及在短短十多年内出现的 RNA 医学平台和临床测试。
最新发现：鉴于之前有大量优秀的综述文章，我们将重点介绍新发现的与未解决的问题有关的内容，包括细胞损伤的机制与遗传模式、APOL1 活性的调节和调制、APOL1 肾脏风险外显率的修饰因子和触发因子、APOL1 相关疾病的多效性谱——所有这些都与治疗进展有关。
综述总结：尽管仍然存在争议和不确定性，但针对 APOL1 mRNA 的使用反义寡核苷酸（ASO）、APOL1 表达抑制剂和专门结合并抑制 APOL1 阳离子流的小分子的有希望的基因组精确治疗方法正在出现，许多已经处于临床试验阶段。这些疗法为减轻 APOL1 肾脏损伤以及可能的其他全身表型提供了巨大的希望。一个挑战将是为可能受益最大的易感个体制定适当使用的指南。
