We owe our long lives to stem cells, which are nestled deep inside certain tissues in the body and constantly replace old cells. In recent years scientists have been able to correct genetic diseases by removing these stem cells, editing their genomes and then implanting them back into the patient, but that adds complications. Now, new research led by Harvard scientists has successfully edited the genes of stem cells while still in the body.
When it comes to treating genetic diseases, it can be kind of like cleaning up pollution in a river. If you just pick up litter downstream, the river will only get dirty again unless you tackle the problem further upstream. In the same way, treating diseased cells won't help much if you don't address the stem cells, which will quickly replace the healthy cells with new diseased ones.
Currently, fixing stem cells involves removing them from their hideouts deep inside the body, then genetically altering them and putting them back into the patient. There are a lot of potential failure points in that complicated procedure: the stem cells can die in the culture dish, the patient's immune system can reject them once transplanted, or they can just fail to fire back up.
"When you take stem cells out of the body, you take them out of the very complex environment that nourishes and sustains them, and they kind of go into shock," says Amy Wagers, lead researcher on the study. "Isolating cells changes them. Transplanting cells changes them. Making genetic changes without having to do that would preserve the regulatory interactions of the cells – that's what we wanted to do."
Building on previous work, the team loaded gene-editing machinery onto different types of adeno-associated viruses (AAVs). These viruses can get into mammal cells, and have been altered so as not to cause disease but instead deliver a payload of gene-editing machinery.
In tests on mice, the researchers used the AAVs to get the CRISPR gene-editing system into different types of skin, blood and muscle stem and progenitor cells. To make it very clear whether the system worked or not, the stem cells were edited to activate "reporter" genes, which would glow a fluorescent red.
And the technique worked. The researchers found that up to 60 percent of the stem cells in skeletal muscle glowed red, indicating they'd been edited, as well as up to 27 percent of skin progenitor cells and 38 percent of stem cells in bone marrow.
Following up, researchers also noted that other dermal cells also appeared to be edited, indicating that changes to the skin stem cells were being passed down the line.
The team says this breakthrough could lead to new treatments for genetic diseases, particularly those like muscular dystrophy which hinge on tissue regeneration.
"So far, the concept of delivering healthy genes to stem cells using AAV hasn't been practical because these cells divide so quickly in living systems – so the delivered genes will be diluted from the cells rapidly," says Sharif Tabebordbar, an author of the study. "Our study demonstrates that we can permanently modify the genome of stem cells, and therefore their progenies, in their normal anatomical niche. There is a lot of potential to take this approach forward and develop more durable therapies for different forms of genetic diseases.
The research was published in the journal Cell Reports.
Source: Harvard