Sick Kids scientists repair genetic errors in trials
Gene editing tool’s success in animal experiments allows researchers to consider human implications
Sick Kids scientists wielding a “breakthrough” gene editing technology have snipped out a genetic defect in mice that causes a severe form of muscular dystrophy, eliminating all signs of paralysis in the animals.
Science magazine hailed the gene editing tool, CRISPR, as the breakthrough of the year in 2015. The new research is part of a wave of effort to push CRISPR from its early experimental promise toward real-life therapies.
“It’s not just something that happens in a petri dish. And it happened in such a remarkable way,” said Dr. Ronald Cohn, the principal investigator of the new study and a senior scientist at Sick Kids.
Much work remains before the technique can be tested in humans. But success in animal experiments allows researchers to begin exploring that next step.
“For the first time it’s possible to think about — and this is still at the thinking stage, let’s be clear — the possibilities of gene correction in humans with these diseases,” said Janet Rossant, a senior scientist in the stem cell and developmental biology program at Sick Kids, who was not involved in the research. Rossant called the new study “really important.”
The mice in the study have a rare and severe form of congenital muscular dystrophy known as MDC1A. Humans afflicted with the disease are typically diagnosed as infants, lose muscle function as they develop, and die in their late teens or early 20s.
The illness is caused by a splice site mutation: A genetic error makes cellular messengers misread a critical section of DNA, like the scratch that makes a record skip.
Researchers in Cohn’s lab used CRISPR to cut out the scratch. Natural cell repair mechanisms stitched the remaining strands of DNA back together, allowing the whole genetic sequence to be read normally.
In followup tests, the mice that received the therapy regained nearly as much hind limb strength and were almost as active as their non-affected peers.
When he saw the degree of recovery in the mice, Cohn says, “I couldn’t believe it. I don’t want to be dramatic, but I couldn’t believe it.”
The research, published online Monday in the journal Nature Medicine, is not the first time a lab has used CRISPR to repair genetic errors in mice with muscular dystrophy.
But the technique Cohn’s team used is particularly simple and efficient, because it does not require the tricky extra step of engineering a new piece of DNA into the genome.
The discovery can potentially be applied to the hundreds of other diseases caused by splice site mutations, from hereditary vision loss to congenital epilepsy.
Amy Wagers, a professor of stem cell and regenerative biology at Harvard University who has used CRISPR to correct different muscular dystrophy mutations in mice, said that Cohn’s results are “quite exciting and compelling.”
“The robustness of the correction we see in animal models to me is very encouraging,” she said.
Wagers’ lab is focusing on one of the safety questions that must be answered before any clinical trial. CRISPR borrows a pair of molecular scissors and a guide mechanism from bacteria. Researchers use those bacterial tools to produce a protein that the body has not been able to generate. How will the immune sys- tem react to these foreign elements?
Scientists are also concerned about whether CRISPR creates unintended mutations elsewhere in the genome, and how to safely deliver these therapies into cells in the body. Humans are much more complicated organisms that mice, and muscles are a much tougher target than blood or bone marrow, which can be removed from the body.
In February, a panel of scientists in the U.S. gave a tentative yellow light to editing DNA in human embryos. “Germline editing” is controversial because any changes would be passed down to future generations; it is banned in Canada.
The research underway in Cohn’s lab is different: they are editing nonreproductive “somatic cells,” ones that have already differentiated into the cells that make up different organs in the body. Another major question Cohn raises is when these therapies must be delivered to have an effect — will they work on patients who are in their teens or 20s?
“To expect that any of these patients who have been sick for so many years are going to get this and stand up from their wheelchair, while I don’t want to say it’s impossible, it’s probably unlikely,” Cohn said.
“Having said that, after speaking with so many patients and their families, if we can just keep them where they are and not have them deteriorate . . . that would already change the world for these patients.”