A research team from the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy, recently published significant findings in Cell Reports Medicine, systematically revealing the potential impact mechanisms of CRISPR-Cas9 gene editing technology on hematopoietic stem cell function and proposing effective optimization strategies. This study provides key scientific evidence for enhancing the safety and efficacy of gene therapy for hereditary blood disorders.

The research was led by Dr. Raffaella Di Micco, group leader at SR-Tiget, in collaboration with experts including Institute Director Prof. Luigi Naldini. The team discovered that during homology-directed repair (HDR) gene editing using AAV6 vectors to deliver repair templates, strong DNA damage responses (DDR) are activated, along with inflammatory signaling driven by p53 and IL-1/NF-κB pathways. "We found that the gene editing process causes some hematopoietic stem cells to exhibit a senescence-like state," explained Dr. Di Micco, "which significantly reduces their ability to long-term reconstitute the blood system after transplantation."

First author Dr. Anastasia Conti further noted: "Most surprisingly, these senescence features persist for months after transplantation, indicating that stem cells retain a 'memory' of the gene editing process." The team validated two complementary optimization strategies through experiments: transient p53 inhibition and the use of the clinically approved IL-1 receptor antagonist Anakinra. Results showed that both methods not only effectively reduce senescence marker levels but also decrease potential genotoxic events.

Dr. Di Micco concluded: "Our study demonstrates that regulating inflammation and senescence-related responses during gene editing can significantly improve the fitness of edited stem cells, achieving more stable and durable therapeutic effects." This discovery provides a scientific explanation for challenges encountered in current gene therapy clinical trials and points the way toward improving treatment outcomes for diseases such as immunodeficiencies and bone marrow failure syndromes.