Gene therapies, used to treat a variety of diseases, are complicated to control, but this discovery makes it easier
The job of the genes in your DNA is to make the proteins your body needs. But genes can be active or inactive, turned on or off. When they are activated, the gene is said to be “expressed.” Now researchers at Baylor College of Medicine have developed a revolutionary system that allows us to control gene expression, allowing our genes to produce therapeutic proteins and control them more precisely. This advance, published in the journal Nature Biotechnology, is a promising step toward safer gene therapies.
The expression of therapeutic genes that are modified to treat or cure diseases must be maintained within an appropriate “therapeutic window.” Too much protein can be toxic, while too little can be ineffective. To date, there has been no safe strategy to implement this therapeutic window in gene therapy, limiting its clinical application.
The research team led by Dr. Laising Yen has been working on this technology for more than a decade, overcoming important barriers to its clinical use. The solution found does not contain any foreign regulatory protein that triggers an immune response in patients. Instead, it uses small molecules that interact with the RNA, generally without triggering an immune response.
A switch in RNA
The system developed uses a “switch” placed in the RNA, the copy of the genetic material that is translated into a protein. This approach makes it possible to control the production of the protein one step earlier by controlling its RNA. To turn protein production on or off, the RNA is modified to contain an additional polyA signal, similar to a “stop signal.” Normally, cells recognize this signal as the end of the RNA. In this system, the polyA signal is placed at the beginning of the RNA, so its detection results in destruction of the RNA and, by default, no protein production until activated by the small molecule.
To activate the gene to the desired level, a section of RNA near the polyA signal is modified so that it can bind to a small molecule, in this case the FDA-approved tetracycline. When tetracycline binds to this section of RNA, it masks the polyA signal and the RNA is translated into protein.
This strategy allows for more precise control of the genetic expression of a therapeutic protein and tailoring its production to disease stages or specific patient needs, all using the FDA-approved tetracycline dosage. Theoretically, it could be used to regulate the expression of any protein and therefore would have many therapeutic applications. Additionally, this system is more compact and easier to implement than existing technologies, so it could also be very useful in laboratories for activating or deactivating a gene of interest to study its function.
REFERENCE
Control of mammalian gene expression by modulating polyA signal cleavage at 5′ UTR in Nature Biotechnology.