First Systemic Delivery of CRISPR in Large Animals Offers Potential for Treating Fatal Muscle Disease

Duchenne muscular dystrophy is caused by a mutation in a key gene for muscle structure and function, resulting in progressive muscle weakness, loss of skeletal and heart muscle integrity, and premature death. Current treatment focuses on controlling the symptoms of muscle loss, however, through the power of CRISPR technology, scientists have found a way to halt disease progression by restoring protein function and improving overall muscle integrity.

The disease causing mutation occurs in a single gene on the X chromosome. This gene encodes for the protein dystrophin, which is responsible for muscle integrity and function. The resulting mutation shifts the reading frame, resulting in early termination of protein translation and a nonfunctional dystrophin protein. In a recent study published in Science, researchers aimed to correct the mutation by skipping exon 51 and restoring the reading frame to produce a functional dystrophin protein.

In order to accomplish this, scientists utilized a canine model that has a naturally occurring, spontaneous mutation analogous to the common mutation causing Duchenne muscular dystrophy in humans. These dogs exhibit many clinical and pathological features of the human disease. In order to reverse the mutation, CRISPR gene editing components were delivered intramuscularly or systemically into the dogs and dystrophin protein levels and muscle structure and function were assessed 6 or 8 weeks later, respectively. Systemic delivery of CRISPR not only restored functional dystrophin protein levels in muscle tissues throughout the body, including bringing the levels close to normal in the heart and skeletal muscle, but also improved overall muscle integrity.

Although these results are promising, this study used a very small sample size and only followed the dogs for a short amount of time. Additional studies to assess safety and long-term effects of gene editing are required. However, it is the first study showing systemic delivery of CRISPR and successful mutation reversal in larger mammals. It is a necessary step towards development of therapeutics for muscular disorders and towards the future of therapeutic gene editing.

How Does Aging Modulate the Expression of SDF1?

Scientists found that older mice have enhanced recruitment of methyltransferase, EZH2, to the SDF1 promoter, which prevents SDF1 gene expression and thus inhibits scar formation. Interestingly, pharmacological inhibition of EZH2 in older mice induced SDF1 and promoted scar formation. Moreover, wounded human skin organoids exhibited age-dependent expression of SDF1 and EZH2 like in the mice, suggesting inhibition of SDF1 can be useful in reducing scar formation following surgery in humans. Currently, SDF1 inhibitors are on the market being utilized to mobilize hematopoietic stem cells. Future studies will focus on utilizing these inhibitors to determine their potential use in preventing scar formation in many types of human tissue injuries, including those suffering from epidermolysis bullosa or in burn victims.

Reference

• Amoasii, L. et al. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science. 2018. DOI: 10.1126/science.aau1549

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