New DART VADAR system allows development of precision RNA-based therapies

DART VADAR can automatically sense and respond to molecular triggers in cells.
Mrigakshi Dixit
Representational image
Representational image

Dr_Microbe / iStock 

During the COVID-19 pandemic, the term mRNA was brought to the public's attention. It is, however, not a new medical technology, having been identified in 1961. 

The rapid development of mRNA-based vaccines saved millions of lives worldwide. Since the beginning of the pandemic, up to twelve billion doses of mRNA vaccines have been administered globally.

These mRNA vaccines were developed to generate a full-body immune response in order to protect the human body from the deadly coronavirus and its variants.

However, developing mRNA-based therapies that could be used for a specific organ or single-cell type has proven difficult. This medical intervention is required because several medical conditions affect a single organ.

A new mRNA system

Researchers at Harvard University's Wyss Institute and MIT have developed a novel mRNA system that can precisely perform this task. Called DART VADAR, it stands for Detection and Amplification of RNA Triggers via ADAR. It is based on an enzyme known as adenosine deaminases acting on RNA, or ADARs.

When this system detects the presence of a specific molecular marker of disease and/or cell type, only then the protein-coding information is translated. Simply put, this sensor can automatically sense and respond to molecular triggers in cells.

“I am particularly excited by the fact that our DART VADAR system is a clinically relevant, compact RNA-based circuit that enables one to direct therapies in a highly programmable manner to specific cell types and cells in certain states, thereby minimizing off-target effects,” said Jim Collins, who led the development of this new technology, in a statement.

They have also carried out some tests to check the working capabilities of the sensor. The researchers used it to look for a single base change in the human p53 tumor suppressor gene. The sensor accurately identified the mutation. Such tests would be critical in developing targeted therapies for cancer patients.

This m-RNA technology has enormous potential and could revolutionize the future of medicine. This novel engineered system, in particular, would broaden the scope of developing RNA-based therapeutics for a wide range of diseases.

They reported the findings in Nature Communications

Study 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.

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