SickKids First to Remove Duplicated Gene Using CRISPR

It’s not often that researchers around the world collectively tout a technology as truly transformational. CRISPR is being called a game changer. It is a gene editing tool more precise, efficient and cheaper than its predecessors, and it is changing the way scientists and clinicians approach the treatment of genetic disorders.

 “CRISPR is the most important technology that I have encountered in my scientific career thus far. Working with patients and families with genetic disorders, I’m often in a position where I can provide a diagnosis, and perhaps supportive care, but no treatment. CRISPR could change that. It could revolutionize the way we care for patients with currently untreatable genetic conditions,” says Dr. Ronald Cohn, principal investigator of the study, and Chief of Clinical and Metabolic Genetics and Co-director of the Centre for Genetic Medicine at SickKids.

Although CRISPR has been widely used as a research tool, its potential in far-reaching therapeutic applications has largely been unexplored, explains Cohn. The study describes how researchers used cells obtained from a patient with Duchenne muscular dystrophy (DMD) to put this technology to the test. Essentially they corrected the mutation that causes Duchenne muscular dystrophy. They used CRISPR like a pair of genetic scissors to not only remove the genetic duplication, but also to fully restore the gene’s function. The result is that the dystrophin protein which is absent in DMD patients was completely restored to its full length, which could have significant impact on future therapeutic developments. Additionally, the study describes multiple applications of this technology as it relates to altering expression of genes or removing certain genetic material for therapeutic purposes.

DMD is a life-limiting, progressive, neuromuscular disorder and currently the only treatment available are corticosteroids, which provide some improvement in muscle function but come with a number of significant side effects.

The cells used in this study were from 14-year-old Gavriel Rosenfeld of the United Kingdom. He was diagnosed with DMD in 2007 when he was just four years old. “It was completely out of the blue. We had no history in our family, and I was not a carrier. We were told that Gavriel would be in a wheelchair by his early teens, would lose upper body function and would likely to die from cardiac or respiratory failure in his early 20s. There was nothing for us to do but give him steroids and physiotherapy. No parent can imagine being given this fatal diagnosis, let alone sitting back and doing nothing about it,” says Kerry Rosenfeld, Gavriel’s mother.

Today, Gavriel no longer walks and is quickly losing upper body function. He can still dress and feed himself but it’s extremely hard for him as his friends become more independent while he is physically declining.

This new research is a major step forward and is exciting not only for clinicians and scientists, but for families like Gavriel’s who are anxiously waiting for a breakthrough and hoping the research moves quickly.

The research is already moving faster than it has in the past because CRISPR has enabled such efficiency. It used to take up to 18 months to create a mouse model; now using CRISPR, it only takes four to five months! The mouse model will be used to study how we can edit the genome in a living organism.

This study demonstrates the proof-of-principle that CRISPR can target disease-causing duplications in the genome. According to Cohn the next step is to re-create Gavriel’s duplication in a mouse model in order to develop a therapy for this particular patient. This is precision, or individualized medicine in action, says Cohn. The biggest challenge however, will be to determine how to deliver the treatment and “edit” the genome in a living being.

“As a clinician-scientist, to be able to help a child with more than just supportive care, and actually think about correcting the genetic mutation is truly paradigm shifting,” says Cohn.

He adds that this paper lays the foundation for further research into the applications of these therapeutic strategies for safe and efficient treatments for many inherited diseases, not just DMD.