Before 2020, it will be difficult to find mRNA therapy topics in the media. Not a new technology discovered in 1961, but the lightning speed of the COVID vaccine has made it to the spotlight, hailed as an incredible scientific feat and condemned as an experimental medical hoax.
Vaccines were the first widely successful treatments using mRNA technology, but researchers have been trying to master targeted therapies for decades. Now scientists believe we are on the cusp of the next step. They identified the detection and amplification of RNA triggers by ADARs, or DART VADARs, by developing a new designed RNA sensing and response circuit that would involve the RNA-editing enzymes ADARs for specific, highly specialized therapeutics. disease or cell type molecular marker.
“Our DART VADAR system is a compact, clinically relevant RNA-based circuit that directs therapy to specific cell types and cells in specific conditions in a highly programmable manner, thereby off-targeting We are particularly excited about the fact that we are able to minimize the effects,” said Jim Collins, core faculty of the Wyss Institute at Harvard University.
The COVID mRNA vaccine, which has been administered more than 12 billion times since its introduction, induces a systemic immune response. The greatest challenge has been to engineer RNA to affect only a single organ or cell type without being rapidly processed by the immune system or causing inflammation outside the target.
Messenger RNA molecules carry the genetic information needed to make proteins. However, their delivery has been difficult to master, as strands of RNA are rapidly degraded in the body and only the recent development of nanoparticles has potentially enabled targeted therapy.
“Our technology arose from the idea that the elements of a responsive RNA sensor (sensing, actuation, etc.) could be decoupled, making it much easier to design circuits for new targets.” Institute. “Ideally, I wanted to be able to change the payload without having to change the sensor element each time.”
ADARs in the DART VADAR system are detected at high concentrations in neurons, but at low levels in other cells. To make sure the sensor works in different types of cells, the researchers added sequences from her ADAR gene to the RNA sensor. Activation of the sensor by natural ADARs then generates more information and creates a positive feedback loop to drive sensor activity (in this case the activity of the signaling molecule is the fluorescent green protein can be observed because it appears).
“What’s really exciting about this sensor is that you can easily replace the green protein signal sequence with the sequence of any therapeutic gene you want to express in response to the presence of a trigger RNA in the cell,” says Kyodo Daiichi. Author Shiva says: Razavi of MIT. “Thus, this sensor can not only detect targets, but also respond automatically without requiring user input, automating the delivery of therapeutic payloads at the cellular level.”
Next, the team tested the DART VADAR system to see if it could detect single-nucleotide mutations in the human p53 tumor suppressor gene, essential for providing targeted therapies to cancer patients. By introducing DART VADAR into human cell line-ups and mutations, the sensor easily and accurately identified abnormalities. DART VADAR then detected molecular differences in cells at different stages of development based on age markers.
As for real-world applications, the team now plans to use DART VADAR to differentiate into stem and other cells, and may one day be used to replace diseased cells in patients. DART VADAR is a step toward overcoming an RNA obstacle that has plagued scientists for decades with the promise of a much more effective way to deliver therapy to patients.
“This team’s ability to combine existing biological building blocks and integrate them into entirely new engineering techniques that have the potential to make treatment of a wide range of diseases faster and easier is a testament to how synthetic biology can transform the world. It’s a great example of how we can change for the better,” said Don Ingber, founder of the Wyss Institute.
The study was published in a journal Nature Communicationsand in the video below you can see the team’s previous work that set them on the path to the new detection and amplification system.
eToehold holds RNA detection control elements for use in RNA therapeutic diagnostics and cell therapy
Source: Wyeth Institute, Harvard University
