Good news! Very clever! mRNA Covid-19 vaccines were only the beginning!
"Using an RNA sensor, ... engineers have designed a new way to trigger cells to turn on a synthetic gene. ...
With this system, we could target very specific disease cells and tissues, which opens up the possibility of identifying cancer cells and then delivering highly potent therapeutics.”
This approach could also be used to develop treatments for other diseases, including viral or bacterial infections ...
Many experimental therapies involving DNA or RNA delivery — such as gene therapy, CRISPR-based therapies, and RNA interference — are currently under development. An important aspect of such therapies is making sure they are turned on only in the target cells, using a programmable control switch. ...
Many experimental therapies involving DNA or RNA delivery — such as gene therapy, CRISPR-based therapies, and RNA interference — are currently under development. An important aspect of such therapies is making sure they are turned on only in the target cells, using a programmable control switch. ...
To achieve that, the researchers harnessed an enzyme that naturally exists in most animal cells, known as adenosine deaminase acting on RNA (ADAR). This enzyme performs base editing of RNA molecules, converting mismatched adenosine bases to inosine. This helps cells to fend off invading viruses, among other functions.
ADAR can detect and repair mismatches in double-stranded RNA, so the researchers designed their sensor RNA construct so that it contains a sequence complementary to their target mRNA but with one mismatch. This draws the attention of ADAR that naturally exists in the cell, which repairs the mismatch.
When ADAR converts adenosine to inosine in the RNA sensor, that edit removes a stop codon in the sequence. After this stop codon is removed, the cell begins reading the RNA construct, which the researchers designed to contain two protein-coding genes. The first is for a reporter molecule — in this case, a fluorescent protein that allows the researchers to see that the synthetic gene was activated. In future versions, this could be replaced by a gene encoding a therapeutic agent. ..."
From the abstract:
"Genetic circuits that control transgene expression in response to pre-defined transcriptional cues would enable the development of smart therapeutics. To this end, here we engineer programmable single-transcript RNA sensors in which adenosine deaminases acting on RNA (ADARs) autocatalytically convert target hybridization into a translational output. Dubbed DART VADAR (Detection and Amplification of RNA Triggers via ADAR), our system amplifies the signal from editing by endogenous ADAR through a positive feedback loop. Amplification is mediated by the expression of a hyperactive, minimal ADAR variant and its recruitment to the edit site via an orthogonal RNA targeting mechanism. This topology confers high dynamic range, low background, minimal off-target effects, and a small genetic footprint. We leverage DART VADAR to detect single nucleotide polymorphisms and modulate translation in response to endogenous transcript levels in mammalian cells."
Fig. 1: Autocatalytic DART VADAR sensors are a practical implementation of ADAR-mediated RNA-responsive translational control
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