Gyroscope Therapeutics Limited, London, UK.
Immunol Rev. 2023 Jan;313(1):402-419. doi: 10.1111/imr.13149. Epub 2022 Nov 12.
The complement alternative pathway (AP) is implicated in numerous diseases affecting many organs, ranging from the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH), to the common blinding disease age-related macular degeneration (AMD). Critically, the AP amplifies any activating trigger driving a downstream inflammatory response; thus, components of the pathway have become targets for drugs of varying modality. Recent validation from clinical trials using drug modalities such as inhibitory antibodies has paved the path for gene targeting of the AP or downstream effectors. Gene targeting in the complement field currently focuses on supplementation or suppression of complement regulators in AMD and PNH, largely because the eye and liver are highly amenable to drug delivery through local (eye) or systemic (liver) routes. Targeting the liver could facilitate treatment of numerous diseases as this organ generates most of the systemic complement pool. This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA-targeting therapeutics ALN-CC5, ARO-C3, and IONIS-FB-LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years.
补体替代途径（AP）与许多影响多种器官的疾病有关，从罕见的血液学疾病阵发性夜间血红蛋白尿症（PNH）到常见的致盲性疾病年龄相关性黄斑变性（AMD）。关键是，AP 放大了任何激活触发下游炎症反应的因素；因此，该途径的成分已成为各种模式药物的靶点。最近，使用抑制性抗体等药物模式的临床试验的验证为 AP 或下游效应物的基因靶向铺平了道路。补体领域的基因靶向目前主要集中在 AMD 和 PNH 中补充或抑制补体调节剂，主要是因为眼睛和肝脏非常适合通过局部（眼睛）或全身（肝脏）途径给药。靶向肝脏可以促进治疗许多疾病，因为该器官产生了大部分系统补体池。本文解释了 RNA 和 DNA 靶向的关键概念，并讨论了替代途径驱动的疾病治疗的临床开发资产，包括 RNA 靶向疗法 ALN-CC5、ARO-C3 和 IONIS-FB-LRX 以及基因疗法 GT005 和 HMR59。这些疗法只是潜在药物候选物的先锋，它们可能在未来几年彻底改变该领域。
