An RNA-Based Switch for Dialing Gene Therapy Up or Down
January 2, 2024
The ability to control the expression of therapeutic genes within a “therapeutic window” is crucial to ensure the development of safe and effective gene therapies, but to date, there has been no control strategy that itself doesn’t have potential safety issues, limiting applications in the clinic. Researchers at Baylor College of Medicine have now described an RNA-based switch, the pA regulator, that they have shown can control mammalian gene expression without generating the unwanted immune responses that are associated with other gene control approaches that use foreign regulatory transactivator proteins. Reporting in Nature Biotechnology on tests with the system in human cells, and in live mice, the researchers say the new technology offers a promising solution that could be applied for clinical gene therapy applications.
Laising Yen, PhD, associate professor of pathology and immunology and of molecular and cellular biology at Baylor, and colleagues, described their work in a paper titled “Control of mammalian gene expression by modulation of polyA signal cleavage at 5′ UTR.”
Just like a doctor adjusts the dose of a medication to the patient’s needs, the expression of therapeutic genes, those modified in a person to treat or cure a disease via gene therapy, also needs to be maintained within a therapeutic window. Staying within the therapeutic window is important as too much of the protein could be toxic, and too little could result in a small or no therapeutic effect.
Although the principle of therapeutic window has been known for a long time, developing a safe method has proven problematic. As the authors noted in their paper, “Current gene transfer methods used in gene and cell therapy, such as adeno-associated virus (AAV), have intrinsic difficulties in executing the ‘conditional’ and ‘reversible’ gene control, which often require further calibrations after delivery.”
And while the commonly used tet-on system is a powerful gene regulation tool in biological studies, its use of foreign regulatory ‘transactivator’ protein can trigger immune responses in nonhuman primates, and so there are no approved clinical applications based on this system. “In fact, immune response against the tet-on system was detected in nonhuman primates, which suggests that the system may not be suitable for clinical applications,” the authors wrote.
