Gladstone’s DNA-editing technique to help cure genetic diseases

The tiniest of genetic changes may lead to some of the most devastating diseases we face today. But scientists at the Gladstone Institutes believe that by treating the human genome like lines of computer code, these harmful mutations could be reversed. This technique might also prove helpful in repairing the damaged code.

The research team, led by Gladstone Investigator Bruce Conklin, claims to have solved one of science and medicine’s most pressing problems: how to accurately capture rare genetic mutations that cause disease (as they can exist at frequencies as low as 1%)—as well as how to fix them.

“Advances in human genetics have led to the discovery of hundreds of genetic changes linked to disease, but until now we’ve lacked an efficient means of studying them,” explained Dr. Conklin. “To meet this challenge, we must have the capability to engineer the human genome, one letter at a time, with tools that are efficient, robust and accurate. And the method that we outline in our study does just that.”

“For our method to work, we needed to find a way to efficiently identify a single mutation among hundreds of normal, healthy cells,” Gladstone Research Scientist Yuichiro Miyaoka, PhD, the paper’s lead author explained.

The team designed a special fluorescent probe to differentiate between mutated sequences and the original sequences. “We were then able to sort through both sets of sequences and detect mutant cells—even when they made up as little one in every thousand cells. This is a level of sensitivity more than one hundred times greater than traditional methods,” Miyaoka added.

These new methods were then applied to induced pluripotent stem cells, or iPS cells. These cells, derived from the skin cells of human patients, have the same genetic makeup as the patient.

In this case, the team said they first used a highly advanced gene-editing technique called TALENs with an aim to introduce a specific mutation into the genome. Some gene-editing techniques, while effective at modifying the genetic code, involve the use of genetic markers that then leave a ‘scar’ on the newly edited genome.

These scars can then affect subsequent generations of cells, thus making future analysis complicated. Athough TALENs are capable of making a clean, scarless single letter edits, these edits are very rare, so that new technique from the Conklin lab is needed.

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