CRISPR Gene Editing in Blood Stem Cells May Induce Premature Aging: New Insights and Solutions

Recent research from the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan has unveiled important findings regarding the use of CRISPR-Cas9 gene editing in blood stem cells. The study highlights that the combination of CRISPR technology with AAV6 vectors can provoke inflammatory responses and cellular senescence, ultimately impairing the long-term regenerative capacity of these cells.

Published in ell Reports Medicine, the research emphasizes the challenges in translating HDR-based gene editing therapies into safe and effective clinical applications for inherited blood disorders. The team, led by Dr. Raffaella Di Micco and in collaboration with European partners, discovered that gene editing activates a DNA damage response, driven by pathways involving p53 and IL-1/NF-, which leads to inflammation and premature aging-like features in hematopoietic stem and progenitor cells.

These senescence-like characteristics persisted even months post-transplantation, indicating a lasting impact of the editing process on stem cell functionality. The team proposed two pivotal strategies to combat this: transiently inhibiting p53 and using anti-inflammatory agents such as Anakinra, an IL-1 receptor blocker. Both methods successfully reduced markers of cell aging and improved the regenerative potential of the edited cells, with Anakinra showing a safer profile by lowering genotoxic risks.

This breakthrough paves the way for enhanced gene therapy approaches that ensure long-term efficacy and safety, especially for conditions requiring durable stem cell engraftment like immunodeficiencies or marrow failure syndromes.

This study underscores the importance of addressing inflammatory and senescence pathways to optimize gene editing therapies, thereby increasing the chances of success in treating genetic blood diseases. For more details, see the full study in ell Reports Medicine source.