Research plan for radiation resistance drugs with CRISPRi

This is like giving people a molecular coat of armor.

Fyodor Urnov

Two teams of scientists in the USA work on anti-radiation drugs based on CRISPR. One of the principal investigators, Jonathan Weissman, shared details of his plan for the study at a conference in Cold Spring Harbor Laboratory.

A year ago, U.S. military agency created a program called PREPARE. Scientists participating in the project try to use methods shared with gene therapies to, well, prepare individuals (in concept: soldiers) for various hazards. Program manager Renee Wegrzyn remarks that they do not aim at changing the human genome. Instead, the goal is to temporarily alter the expression of genes with interference methods, such as CRISPRi and various types of RNA molecules.

An especially exciting part of the project tackles exposure to radiation. Detrimental electromagnetic waves easily mutate our DNA, leading to the death of cells, as well as a higher incidence of cancer. Scientists will try to prevent changes in the human genome with CRISPRi, instead of modifying it. The initiative was described from the big-picture perspective in a long read at OneZero here.

Weissman showed technical details of their approach. He divides the project into four phases: 1. identification, 2. optimization, 3. validation, 4. clinical test.

The first phase, probably already in progress, uses a genetic screen to identify genes, which contribute to radiation resistance. Systematic mutations of all interesting genes and subsequent exposure to radiation can reveal changes lowering the survival – therefore, point to the genes playing an essential role in preventing and correcting DNA damage.

In the second phase, scientists will design and optimize guides of CRISPRi, which will accurately target selected genes. As they describe, the aim is to change multiple genes at once – to achieve high redundancy. The third phase will move the focus from CRISPR systems to delivery methods. At this moment, researchers consider adeno-associated viruses and liposomes. Those methods will be tested in animal models, which will then allow the project to move to the last phase – proposing an investigative new drug to the FDA.

DARPA aims to enter clinical trials before the end of the project in 2022/2023.

Sources: DARPA, James Madison University Center for Genome & Metagenome Studies
Photo: Nuledo

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