Chronic kidney disease is one of the leading causes of mortality worldwide because of kidney failure and the associated challenges of its treatment including dialysis and kidney transplantation. About one-third of chronic kidney disease cases are linked to inherited monogenic factors, making them suitable for potential gene therapy interventions. However, the intricate anatomical structure of the kidney poses a challenge, limiting the effectiveness of targeted gene delivery to the renal system. In this review, we explore the progress made in the field of targeted gene therapy approaches and their implications for rare genetic kidney disorders, examining preclinical studies and prospects for clinical application. In vivo gene therapy is most commonly used for kidney-targeted gene delivery and involves administering viral and nonviral vectors through various routes such as systemic, renal vein, and renal arterial injections. Small nucleic acids have also been used in preclinical and clinical studies for treating certain kidney disorders. Unexpectedly, hematopoietic stem and progenitor cells have been used as an ex vivo gene therapy vehicle for kidney gene delivery, highlighting their ability to differentiate into macrophages within the kidney, forming tunneling nanotubes that can deliver genetic material and organelles to adjacent kidney cells, even across the basement membrane to target the proximal tubular cells. As gene therapy technologies continue to advance and our understanding of kidney biology deepens, there is hope for patients with genetic kidney disorders to eventually avoid kidney transplantation.

中文翻译：

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罕见遗传性肾病的靶向基因治疗


慢性肾病是全球死亡的主要原因之一，因为肾衰竭及其治疗（包括透析和肾移植）的相关挑战。大约三分之一的慢性肾病病例与遗传性单基因因素有关，使其适合潜在的基因治疗干预。然而，肾脏错综复杂的解剖结构构成了挑战，限制了靶向基因递送到肾脏系统的有效性。在这篇综述中，我们探讨了靶向基因治疗方法领域取得的进展及其对罕见遗传性肾病的影响，研究了临床前研究和临床应用前景。体内 基因疗法最常用于肾脏靶向基因递送，涉及通过各种途径（如全身、肾静脉和肾动脉注射）施用病毒和非病毒载体。小核酸也已用于临床前和临床研究，用于治疗某些肾脏疾病。出乎意料的是，造血干细胞和祖细胞已被用作肾脏基因递送的离 体基因治疗载体，突出了它们在肾脏内分化为巨噬细胞的能力，形成隧道纳米管，可以将遗传物质和细胞器递送到邻近的肾细胞，甚至穿过基底膜靶向近端肾小管细胞。随着基因治疗技术的不断进步和我们对肾脏生物学的理解加深，遗传性肾病患者有希望最终避免肾移植。