Newly developed RNA tool can illuminate brain circuits and even edit specific cells

Scientists at Duke University have developed an RNA-based editing tool that targets individual cells, not genes. It can precisely target any type of cell and selectively add any protein of interest. The researchers say the tool could enable the modification of very specific cells and cellular functions to manage disease.

Using an RNA-based probe, a team led by neurobiologist Z. Josh Huang, Ph.D., and postdoctoral researcher Yongjun Qian, Ph.D., demonstrated that they could introduce a fluorescent tag into cells to label specific types of brain tissue; a light-sensitive switch , to silence or activate neurons of their choice; even a self-destructing enzyme to precisely clear some cells and not others. The work will be published today (October 5, 2022) in the journal Nature.

Their selective cell monitoring and control system relies on ADAR enzymes, which are found in every animal’s cells. While these are in the early stages of CellREADR (cellular access via RNA sensing of endogenous ADARs), the possible applications seem endless, Huang said, as is its potential to work across the animal kingdom.

“We are excited because this provides a simplified, scalable and generalizable technology to monitor and manipulate all cell types in any animal,” Huang said. “We can actually modify the function of specific types of cells to manage disease,” said Huang. Regardless of its initial genetic predisposition. This is not possible with current treatments or drugs.”

CellREADR is a string of customizable RNAs composed of three main parts: a sensor, a stop signal, and a set of blueprints.

First, the research team decides on the specific cell type they want to study and identifies the target RNAs that are uniquely produced by that cell type. The tool’s remarkable tissue specificity relies on the fact that each cell type produces signature RNAs that other cell types do not.

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A sensor sequence is then designed to act as the complementary strand of the target RNA. Just as the ladder on DNA is made up of complementary molecules that are themselves attracted to each other, RNA has the same property that behaves like a magnet, and if it has a matching molecule, it can attach to another piece of RNA.

After a sensor enters the cell and finds its target RNA sequence, the two pieces of RNA stick together, forming a sheet of double-stranded RNA. This new mess of RNA triggers the ADAR enzyme to examine the new creation and then change a single nucleotide of its code.

ADAR enzymes are a cellular defense mechanism designed to edit double-stranded RNA as it occurs, and are thought to be present in all animal cells.

Knowing this, Qian designed CellREADR’s stop flag using the same specific nucleotides that ADAR edits in double-stranded RNA. The stop flag that prevents the protein blueprint from being built is removed only when CellREADR’s sensor is docked with its target RNA sequence, making it highly specific for a particular cell type.

Once ADAR removes the stop flag, the blueprint can be read by the cellular machinery to build new proteins within the target cell.

In their paper, Huang and his team put CellREADR through its own grind. “I remember two years ago, when Yongjun built the first iteration of CellREADR and tested it in mouse brains,” Huang said. “To my amazement, he achieved amazing results on the first try.”

The team’s careful planning and design paid off, as they were then able to demonstrate that CellREADR accurately labeled specific brain cell populations in living mice, as well as effectively adding instructions for activity monitors and control switches. It also worked well in rats and human brain tissue collected from epilepsy surgery.

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“With CellREADR, we can pick populations to study and really start looking at the full range of cell types that exist in the human brain,” said co-author Derek Southwell, PhD, a neurosurgeon and assistant professor in Duke’s Department of Neurosurgery .

Southwell hopes CellREADR will improve his and others’ understanding of the circuits of the human brain and the wiring diagrams of cells within it, and in doing so, help advance new treatments for neurological diseases, such as one he is experimenting with for drug resistance Promising new approach to epilepsy.

Huang and Qian are particularly confident and hopeful about CellREADR’s potential as a “programmable RNA drug” to potentially cure disease, because that’s what drew them to their scientific work in the first place. They have filed a patent for the technology.

“When I majored in pharmacology as an undergraduate, I was very naive,” Qian said. “I thought a lot of things could be done, like curing cancer, but it’s actually very difficult. However, now I’m thinking, yes, maybe we can do it.”

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