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Sick Kids Researchers Use CRISPR/Cas9 to Remove Duplications in Duchenne Muscular Dystrophy

NEW YORK (GenomeWeb) – Scientists from Toronto's Hospital for Sick Children (Sick Kids) have led a study showing several ways in which CRISPR/Cas9 genome editing could be used to treat hereditary diseases. Among the various applications demonstrated, the researchers used CRISPR/Cas9 to remove exon duplication in a gene affecting a patient with Duchenne Muscular Dystrophy (DMD), leading to the production of regular dystrophin.

Led by co-first authors Daria Wojtal and Dwi Kemaladewi and senior authors Evgueni Ivakine and Ronald Cohn, the scientists published their study yesterday in the American Journal of Human Genetics. In addition to removing the duplication in the dystrophin gene in cells taken from a 14 year-old patient diagnosed with DMD, the scientists were able to use a Cas9 protein modified to promote gene expression to increase the amount of utrophin, a disease-ameliorating protein for DMD. Furthermore, they were able to disrupt a specific allele carrying a dominant-negative mutation in fibroblasts of an individual affected by achondroplasia – a kind of dwarfism - and remove a large chromosomal rearrangement in primary cells taken from an individual with an X chromosome duplication.

DMD is an X chromosome-linked disorder characterized by deficiency of the protein dystrophin, an important component of muscle tissue. Duplications of one or more exons in the dystrophin gene account for approximately 10 percent of DMD-causing mutations.

"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," Cohn said in a statement. "CRISPR could change that."According to a statement from Sick Kids, corticosteroids are the only treatment available to patients with DMD.

Though other researchers are evaluating several gene therapies for DMD, such as delivering a truncated dystrophin gene or exon skipping, the Sick Kids researchers said that removing exon duplications had not been well studied.

"Shorter dystrophin product ameliorates the disease phenotype only to the extent of making it similar to that of individuals affected by Becker muscular dystrophy, where a truncated yet functional dystrophin protein is detected," the authors wrote.

The researchers designed guide RNAs to target exons 18-30 in the dystrophin gene, delivering the CRISPR/Cas9 system with a lentiviral vector. They said the intervention led to the production of full-length dystrophin.

The researchers said they hoped their proof-of-concept studies could help lay the foundation for further research, eventually leading to in vivo treatments for inherited diseases. 

"CRISPR is the most important technology that I have encountered in my scientific career thus far," Cohn said. "It could revolutionize the way we care for patients with currently untreatable genetic conditions."