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New RNA therapy can be used for virus diagnosis and cancer treatment
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New RNA therapy can be used for virus diagnosis and cancer treatment.
Next-generation RNA therapy is born, which can realize RNA therapy, virus diagnosis and cancer treatment.
In our cognition, DNA is the carrier of genetic information, protein is the main bearer of life functions, and RNA is the transfer hub between the two. However, the structural complexity and relative stability of RNA also make scientists believe that this biological material is the basis for new treatments, synthetic biomarkers and vaccines. In the COVID-19 pandemic, the development and application of mRNA vaccines have been Prove this.
If we synthesize an RNA molecule that carries therapy, diagnosis, or other functions, and deliver it to the cell, then we can instruct the cell to produce the protein it needs and perform the corresponding function.
But in this process, a key challenge facing researchers is how to ensure that only those cells that cause or are affected by specific diseases will express this protein. This ability can help the side effects of RNA targeted therapy.
Recently, a research team from Harvard University and the Massachusetts Institute of Technology (MIT) published a research paper entitled: RNA-responsive elements for eukaryotic translational control in the journal Nature Biotechnology .
This research designed a new RNA therapy technology – eToeholds , which can selectively initiate gene therapy of target cells (including human cells) , and only when cell-specific or specific viral RNA exists, the related protein codes The sequence can be expressed.
This will guide the development of application platforms for RNA-targeted gene therapy, virus diagnosis, and cancer treatment.
Professor James Collins , the corresponding author of this study, said: “This brings a new control circuit to the emerging field of RNA therapy-the treatment can be initiated in specific tissue cells to achieve more specific and safer RNA therapy and diagnostic methods.
More importantly, eToeholds technology not only opens up the next generation of RNA therapy, but also applies to plants and other higher organisms, becoming a new basic research and synthetic biology research tool. “
Toehold switch for bacteria
As early as 2014, James Collins and others successfully developed Toehold switches in bacteria . They respond to specific trigger RNAs and initiate the synthesis of required proteins through the bacterial protein synthesis mechanism. The results of this research were published in the Cell Journal.
The system works by introducing a Toehold RNA molecule that binds to the ribosome binding site of the mRNA molecule encoding a specific protein.
This binding prevents the translation of the target mRNA molecule because it cannot attach to the ribosome.
At the same time, Toehold RNA also contains another sequence, which can be combined with another trigger mRNA sequence as a trigger.
If the target mRNA sequence is detected, the Toehold switch will be turned on, and the blocked protein translation process can continue.
This triggering mRNA sequence can be any gene, such as a fluorescent reporter molecule.
This fluorescent signal provides researchers with a visual method to determine whether the target mRNA sequence is detected.
Eukaryotic Toehold switch-eToeholds
Unfortunately, the bacterial Toehold switch cannot be applied to human cells with more complex structures and protein synthesis devices.
Therefore, in this new study, the research team began to try to create a similar “Toehold switch” that can be used in human cells.
Since gene translation in eukaryotic cells is more complicated, the genetic components they use in bacteria cannot be introduced into human cells.
The research team turned its attention to the system in which viruses hijack eukaryotic cells to translate their own viral genes—the internal ribosome entry site (IRES)—which can directly recruit ribosomes to translate mRNA into protein.
Dr. Evan Zhao , the first author of the study , explained: “This is a complex RNA folding structure. The virus has developed to hijack the ribosome because the virus needs to find a way to express the protein.”
Design and schematic of eToeholds
Researchers started with IRES naturally produced in different types of viruses and inserted them into Toehold switches to develop RNA-based eukaryotic Toehold switches, which the research team named eToeholds .
When the eToeholds switch is transferred to a human cell, it will prevent the expression of the target gene unless the triggering mRNA molecule is detected in the cell.
Gene therapy, virus detection and cancer treatment platform based on eToeholds
In the process of rapid iteration, scientists can design and optimize eToeholds that are functional in human and yeast cells, as well as cell-free protein synthesis analysis. They used this technology to develop the detection of various triggers in human and yeast cells.
For example, they found that the mRNA codes of Zika virus and SARS-CoV-2 can be detected. The researchers further pointed out that one possible application of this technology is to design T cells to detect and respond to the mRNA of the new coronavirus and other popular viruses during infection.
Dr. Evan Zhao said: “We have further demonstrated that stable cell lines expressing eToeholds can be used to detect natural viral infections ( Zika virus) and viral transcripts (SARS-CoV-2) .
We also proved that eToeholds can be based on endogenous The sexual RNA level selectively activates protein translation, thereby distinguishing different cell states and cell types.”
eToeholds detects Zika virus
Not only that, the research team also designed eToeholds that can detect the naturally-produced protein mRNA in human cells, which helps reveal cell states, such as endoplasmic reticulum stress.
As an example, the researchers showed that they can detect the expression of heat shock proteins, which are usually produced when cells are exposed to high temperatures.
In addition, the researchers also proved that cancer cells can be identified by detecting the eToeholds of tyrosinase mRNA , an enzyme that produces excess melanin in melanoma cells.
This targeting can allow researchers to develop a treatment that triggers cell death when cancerous proteins are detected in cells.
eToeholds recognizes melanoma cells
Angelo Mao , the co-first author of the study, said: “Our idea is to target any unique RNA markers and provide treatments.
More importantly, eToeholds and the sequences encoding the required proteins can be designed as more stable DNA molecules.
After being introduced into the cell, these DNA molecules will be converted into RNA molecules, which greatly increases the possibility of eToeholds being delivered to the target cell.”
Professor James Collins said: “The eToeholds platform can help targeted RNA therapy and some gene therapies for specific cell types. This is very important because the clinical application of many nucleic acid targeted therapies is hindered by excessive off-target toxicity. eToeholds technology can be based on mRNA signals to translate proteins or protein-based precursors, which will help solve this challenge by limiting the activation of specific target cells that require treatment.”
All in all, this research has developed an eToeholds system that can be expressed in eukaryotic cells, which can perform functions such as gene therapy, virus detection and even cancer treatment in specific cells and tissues based on the presence or absence of triggering mRNA molecules.
Open up the next generation of RNA therapy, and is expected to become a new research tool for basic research and synthetic biology.
New RNA therapy can be used for virus diagnosis and cancer treatment
(source:internet, reference only)