Duchenne muscular dystrophy (DMD) is one of the most common and most devastating muscular diseases, greatly reducing patients’ quality of life and life expectancy. Now, researchers in Germany have managed to use the CRISPR gene-editing tool to correct the condition in pigs, bringing the treatment ever closer to human trials.
A protein called dystrophin is necessary for muscles to regenerate themselves, but people with DMD have a genetic mutation that removes the gene that produces dystrophin. That means that affected children usually begin to show symptoms of muscle weakness by age five, lose the ability to walk by about age 12, and rarely live through their 30s as their heart muscles give out.
Because it’s a genetic condition, DMD is a prime target for treatment with the gene-editing tool CRISPR. This system is prized for its ability to cut out problematic genes and replace them with more beneficial ones, and has been put to work treating cancer, HIV and forms of blindness.
In experiments in pigs, the researchers on the new study used CRISPR to correct the faulty dystrophin gene. That allowed the pigs to once again produce dystrophin proteins – although they were shorter than usual, they were still stable and functional. That improved the animals’ muscle function and life expectancy, and made them less likely to develop an irregular heartbeat.
Importantly, this treatment avoids one of the main issues with CRISPR gene-editing – transience. Most cells in the body will die off at some point, being replaced by others of the same type, so those that have been edited will eventually just disappear, rendering the treatment ineffective. But heart and muscle (myocardial) cells are long-lived, so by performing the edits in these the effects will stick around much longer.
“One half of all myocardial cells remain functional from birth throughout the entire lifecycle of a human being," says Christian Kupatt, lead author of the study. "The genome of a cell is used for protein biosynthesis as long as the cell is alive, and once a cell has been affected by the therapy, it remains corrected. So if we change the genome of a myocardial cell, the correction is a long-term success, in contrast to the results of previous methods.”
Previous experiments have used CRISPR to correct DMD – it was tested in mice in 2014, and dogs in 2017 – but this study marks the first time the treatment has been tested in pigs. These animals are biologically much closer to humans, so the team says that the new model is a major step towards clinical trials for DMD gene therapy.
The research was published in the journal Nature Medicine.
Source: Technical University of Munich