Targeted gene therapy for rare genetic kidney diseases

Kidney Int. 2024 Dec;106(6):1051-1061. doi: 10.1016/j.kint.2024.07.034. Epub 2024 Aug 31.

Abstract

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.

Keywords: adeno-associated viral (AAV) vector; ex vivo gene therapy; hematopoietic stem and progenitor cells; in vivo gene therapy; lentiviral vector; lipid nanoparticles.

Publication types

  • Review

MeSH terms

  • Animals
  • Gene Transfer Techniques
  • Genetic Therapy* / methods
  • Genetic Vectors*
  • Humans
  • Kidney / pathology
  • Kidney Diseases / genetics
  • Kidney Diseases / therapy
  • Rare Diseases / genetics
  • Rare Diseases / therapy
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / therapy