The ability to correct disease-causing genetic mistakes using genome editors holds great promise in medicine, but it is not without risk. When this type of “genetic surgery” is performed on DNA, for instance, there is always the danger of leaving permanent genetic scars that may even be heritable.<\/p>\n
To alleviate this risk, researchers have experimented with gene editing processes on messenger RNA (mRNA), a central link between DNA and proteins that doesn’t carry the same risks because it doesn’t involve permanent changes to the DNA. But existing RNA editing tools have proven either too cumbersome to use or too toxic to human cells.\u00a0<\/p>\n
Yale researchers have developed a new – and safe – family of RNA-editing tools that utilize an RNA-targeting activity that they found “hidden” inside a popular gene editing tool known as CRISPR-Cas9.\u00a0<\/p>\n
<\/p>\n
The solution was surprisingly simple. We discovered robust RNA-targeting activity hidden inside [the CRISPR tool] and its related enzyme, IscB, and simply unleashed its hidden power to target RNA.”\u00a0<\/p>\n
\n
<\/p>\n
Ailong Ke, study lead author,\u00a0professor of molecular biophysics and biochemistry at Yale School of Medicine and member of Yale’s Faculty of Arts and Sciences<\/p>\n
<\/p>\n
Their findings were published in the journal\u00a0Cell.<\/p>\n
CRISPR (clustered regularly interspaced short palindromic repeats) are\u00a0DNA sequences found in the genomes\u00a0of\u00a0organisms – such as\u00a0bacteria\u00a0and archaea –\u00a0whose cells lack a nucleus and other membrane-bound organelles.\u00a0Cas9\u00a0(CRISPR-associated protein 9) is an\u00a0enzyme\u00a0that uses CRISPR sequences. Cas9 enzymes and CRISPR sequences form the basis of the\u00a0CRISPR-Cas9\u00a0technology used to\u00a0edit genes in living organisms.<\/p>\n
The approach was guided by “a deep understanding of the molecular structures of IscB,” including findings reported by the lab in the journal Science, said\u00a0Chengtao Xu, a postdoctoral associate at Yale and first author of the study.<\/p>\n
“It would be much harder to come up with the same idea from Cas9, because its structure is way more sophisticated than IscB.” said Xu. “Nature leaves a lot of treasures for us, and it’s challenging but intriguing to reveal them.\u00a0This is something we’re particularly good at in molecular biophysics and biochemistry.”<\/p>\n
Researchers named their new tools R-IscB and R-Cas9 and defined their usage in genome research and medicine.<\/p>\n
“They are the Swiss army knives for RNA editing,” Ke said. “We show that they can be used to perturb mRNA functions, to slice and destroy the targeted mRNA, or to correct the coding mistakes in the mRNA target.<\/p>\n
“In essence, we have a way to perform any type of genetic surgery at the RNA level, which is a big deal.”<\/p>\n
Xu added that the tools worked just as well on the enzyme Cas9 targets, which use\u00a0CRISPR sequences. “We’re really excited to see how far we can take this approach with other similar tools,” he said.\u00a0<\/p>\n
Researchers now plan to test the tools in the lab to cure rare genetic diseases or to promote wound healing.<\/p>\n
“We’re particularly excited about the trans-splicing reactions performed by the R-IscBs, because it can potentially correct any\u00a0type of genetic mutations at the RNA level. This is\u00a0a\u00a0huge opportunity for genome medicine,” Ke said.\u00a0<\/p>\n
“There are a lot of potential applications. The new tool is robust, very precise, and quite versatile.”<\/p>\n
Other\u00a0study authors include Xiaolin Niu and Haifeng Sun, who are postdoctoral associates at Yale. The study also involved collaborator\u00a0Professor Weixin Tang\u00a0from the University of Chicago.<\/p>\n
Source:<\/p>\n
Journal reference:<\/p>\n