Researchers have shown that a new gene-editing treatment stops Duchenne muscular dystrophy in dogs.
Duchenne muscular dystrophy (DMD) is a devastating illness that affects about one in 5,000 boys. It is caused by various combinations of coding errors in the large gene that is responsible for the production of the protein dystrophin. Dystrophin is largely located in the skeletal and heart muscles, but some is also present in nerve cells in the brain. In muscle cells, the protein is part of a protein complex that strengthens muscle fibers and protects muscles from injury by connecting the cytoskeleton of the cell with the extracellular matrix. In nerve cells, dystrophin is thought to play a role in the structure and function of synapses.
Boys with DMD do not produce dystrophin. They experience progressive muscle weakness and wasting (atrophy) and a heart condition called dilated cardiomyopathy. As a result, they lose the ability to walk and eventually die of heart failure. There is currently no cure for the disease.
Because DMD is caused due to problems with genetic coding, there has been great interest in the development of a gene therapy as a cure. The challenge has been the very large size of the gene involved, which makes it difficult to transport using viruses. In addition, more than 3,000 different mutations can cause muscular dystrophy.
Researchers at the University of Texas Southwestern Medical Center have used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing technology to cure DMD in dogs. They reported their latest results at a recent conference at the National Institutes of Health.
The researchers developed guided ribonucleic acids (RNAs) that deliver the edited Cas9 enzyme to 12 designated splice sites, avoiding editing at undesired locations. The sites were chosen because they are “hot spots” along the dystrophin gene where up to 60 percent of the disease-causing mutations occur; it is a practical way to treat many mutations at one time with a single edit.
The team previously corrected a single gene mutation that caused DMD in mice. In their latest study, dogs were bred to have DMD. The CRISPR-based treatment was infused into the bloodstreams of one-month-old puppies. The guided RNAs reached the targeted muscle cells and correctly edited the dystrophin gene, providing “striking” results, according to the scientists.
The research is supported by the biotech company Exonics, which was started by the patient advocacy group CureDuchenne in 2017 and has raised more than $40 million. The success in such large mammals as dogs, suggests that the gene editing technology may also be effective in humans. The initial focus is on the exon 51 region of the dystrophin gene, which if repaired could help approximately 13% of DMD patients, and investigation of potential side effects.