A collaborative team from Arc Institute, Gladstone Institutes, and UCSF has unveiled a groundbreaking epigenetic editing platform that could revolutionize next-generation cell therapies. Published in Nature Biotechnology on October 21, 2025, and reported on World Pharma News, the study introduces a method to safely and efficiently reprogram human T cells using CRISPRoff and CRISPRon—tools that modify gene expression without altering the DNA sequence.
Traditional gene editing methods, while powerful, often pose risks such as DNA damage and cell toxicity, especially when multiple genes are edited simultaneously. This has been a major hurdle in developing more resilient T cell therapies, particularly for solid tumors that exhaust immune cells. The new platform bypasses these issues by using epigenetic tags to silence or activate genes, preserving cell viability even when editing several targets at once.
CRISPRoff works by adding methylation marks to suppress genes that limit T cell function, while CRISPRon removes these marks to enhance beneficial gene activity. Remarkably, the effects of these modifications persist through numerous cell divisions and immune responses, even though the editing tools are only present for a short time.
To showcase the platform’s potential, researchers engineered CAR-T cells with enhanced cancer-fighting capabilities. By silencing the RASA2 gene, a known inhibitor of T cell activation, alongside receptor insertion, the modified cells demonstrated superior performance in lab tests and mouse models of leukemia. These dual-edited cells maintained their potency over time, unlike conventional CAR-T cells which became exhausted.
The study’s senior authors, including Dr. Alex Marson and Dr. Luke Gilbert, emphasize the broader implications of combining genetic and epigenetic engineering. This approach not only improves cancer therapies but also opens doors to treating autoimmune diseases, enhancing transplant outcomes, and more.
Importantly, the platform integrates seamlessly with existing CAR-T manufacturing protocols, suggesting a clear path toward clinical application. First author Laine Goudy notes that the data may support direct progression to human trials for certain uses.
This innovation marks a significant step forward in scalable, programmable cell therapies, offering new hope for patients facing complex diseases where traditional approaches fall short.
