Home Medizin Durch kleine Moleküle schaltbare RNA-Plattform ermöglicht die Kontrolle der therapeutischen Proteinexpression

Durch kleine Moleküle schaltbare RNA-Plattform ermöglicht die Kontrolle der therapeutischen Proteinexpression

von NFI Redaktion

Gene therapy uses therapeutic genes to treat or cure diseases, and it is crucial to keep the expression of these genes within a therapeutic window, similar to a doctor adjusting the dosage of a medication to suit a patient’s needs. It is important to stay within this therapeutic window as too much protein could be toxic, and too little could be ineffective in achieving the desired therapeutic effect.

While the concept of the therapeutic window is well-established, there has been a lack of a safe strategy to effectively implement it in clinical gene therapy applications. However, researchers at Baylor College of Medicine have developed a technology to address this issue without using foreign regulatory proteins that may trigger an immune response in patients. This breakthrough is reported in their recent study published in the journal Nature Biotechnology.

Dr. Laising Yen, corresponding author and associate professor in Baylor’s Department of Pathology and Immunology as well as the Department of Molecular and Cellular Biology, explains, „Current gene regulation systems in mammalian cells have not received approval by the US FDA for clinical applications, primarily because they employ a regulatory protein that is foreign to the human body and triggers an immune response. This means that cells expressing the therapeutic protein would be attacked, eliminated, or neutralized by the patient’s immune system, rendering the therapy ineffective.“

– Dr. Laising Yen

Yen and his team have worked for over a decade on developing this technology and have now achieved a solution to overcome the major obstacles associated with its clinical application. The developed system does not use foreign regulatory proteins that could trigger an immune response. It uses small molecules to interact with RNA and does so within the FDA-approved dosage.

A Genetic On/Off Switch

The researchers at Baylor College of Medicine have successfully developed a system to activate genes using FDA-approved dosages of small molecules. This system functions as an on/off switch for gene expression, allowing for precise control over the production of therapeutic proteins.

By manipulating the RNA of interest to contain an additional PolyA signal, similar to a „stop sign“ genes use to mark the end of a gene, the research team was able to develop a sophisticated mechanism. This mechanism allows for the control of protein production by altering RNA, effectively turning the gene on and off.

For instance, if a patient requires only a small amount of therapeutic protein, they would consume a small dose of Tetracycline to activate the therapeutic genes. Conversely, if they need more therapeutic protein, they would consume a higher dose of Tetracycline to increase the production of the protein. The system also allows for the flexibility to fine-tune protein expression levels to cater to the specific needs of the patient.

This precise control over gene expression represents a significant advance in gene therapy, providing options to adapt production to disease progression or the specific needs of the patient—all using FDA-approved doses of Tetracycline.

It is important to note that this approach is not disease-specific and has the potential for numerous therapeutic applications, offering a higher level of flexibility and ease of implementation compared to existing technologies. This suggests that the system may have substantial utility in the lab and for future clinical applications.

Liming Luo, Jocelyn Duen-Ya Jea, Yan Wang, and Pei-Wen Chao, all from Baylor College of Medicine, also contributed to this work.

The study was supported by an E&M Foundation Pre-Doctoral Fellowship for Biomedical Research, NIH Grants (R01EB013584, UM1HG006348, R01DK114356, R01HL130249, P30 CA125123, and S10 RR024574), a Biogen SRA, departmental start-up funds at the Department of Pathology and Immunology at Baylor College of Medicine, and a CPRIT Core Facility Support Award CPRIT-RP180672.


Baylor College of Medicine

Journal reference:

Luo, L., et al. (2024). Control of mammalian gene expression by modulation of PolyA signal cleavage at the 5′-UTR. Nature Biotechnology. doi.org/10.1038/s41587-023-01989-0.

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