Key Points
- Researchers demonstrated that focused ultrasound–inducible CRISPR enabled precise, noninvasive genetic editing.
- Combining focused ultrasound with CRISPR could enhance CAR-T cell therapy while reducing the risks of off-target effects.
A study published in Nature Communications combined focused ultrasound with CRISPR technology, creating a precise, noninvasive method to manipulate genes. CRISPR is a Nobel-prize winning gene-editing technology that allows scientists to precisely alter DNA sequences within living beings. However, CRISPR therapy has limitations in human applications. Off-target effects, causing unintended genetic changes, pose significant safety risks. Additionally, delivering CRISPR components to specific cells or tissues remains a challenging task, particularly in complex human diseases.
In this study, focused ultrasound–inducible CRISPR (FUS-CRISPR) was shown to be capable of upregulating, downregulating, or deleting specific genes in cells. The investigators relied on focused ultrasound to noninvasively heat tissue and activate a heat-sensitive promoter, triggering CRISPR activity in the targeted area. FUS-CRISPR was then used to prime tumors for immune-based treatment, which significantly enhanced the efficacy of chimeric antigen receptor (CAR)-T cell therapy. This synergy offers new hope for the treatment of complex cancers.
Focused ultrasound offers a novel solution by enabling noninvasive and localized activation of CRISPR systems, minimizing the risk of off-target effects and ensuring that gene editing is confined to the intended tissues. In the context of cancer, the development of FUS-inducible CRISPR tools introduces an innovative strategy that enables localized and precise genomic editing that can be used to disrupt tumor defenses while minimizing harm to healthy tissues.
“This research exemplifies how we can transform cancer treatment by integrating cutting-edge technologies like focused ultrasound and CRISPR,” said Yingxiao Wang, PhD, the principal investigator, in a press release. “By enabling targeted, noninvasive therapies, we are opening new doors for addressing even the most resistant forms of cancer.”
Dr. Wang and his team demonstrated that FUS-CRISPR effectively disrupted genetic structures called telomeres in tumor cells. This telomere disruption triggered cellular aging and immune activation, making the tumors more vulnerable to CAR-T cells. When combined, FUS-CRISPR and CAR-T cells provided a significant survival benefit for mice treated with both technologies, highlighting the potential for enhanced cancer treatment strategies.
The synergy of these two technologies opens doors for treating cancers that have been resistant to conventional methods, potentially changing the trajectory of outcomes for countless patients.
“This study introduces a new set of sonogenetics-based CRISPR tools controlled by focused ultrasound, significantly expanding its potential in gene and cell therapy,” said Frederic Padilla, PhD, director of the Foundation’s Gene and Cell Therapy Program. “Other novel approaches for precise and multiplexed genome regulation, such as using a heat-shock promoter–controlled CRISPR-Cas12a system activated by focused ultrasound or using focused ultrasound–based blood-brain barrier opening to deliver of viral and non-viral vectors carrying gene editing tools (See Kwak et al. and Yeh-Hsing et al.), allow for precise targeting and ensure the delivery and action of gene editing tools at a specific brain area.”
Dr. Padilla went on to say, “Together, all of these studies highlight the considerable potential of focused ultrasound for precise, noninvasive, and spatiotemporally controlled gene modulation and delivery. We look forward to the clinical translation of these versatile approaches, which could enable safer and more effective in vivo gene editing and cell therapies.”
For more details, read “Ultrasound Control of Genomic Regulatory Toolboxes for Cancer Immunotherapy” in Nature Communications (open source).
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