Posted on by Dr. Francis Collins
Thanks to CRISPR and other gene editing technologies, hopes have never been greater for treating or even curing Duchenne muscular dystrophy (DMD) and many other rare, genetic diseases that once seemed tragically out of reach. The latest encouraging news comes from a study in which a single infusion of a CRISPR editing system produced lasting benefits in a mouse model of DMD.
There currently is no way to cure DMD, an ultimately fatal disease that mainly affects boys. Caused by mutations in a gene that codes for a critical protein called dystrophin, DMD progressively weakens the skeletal and heart muscles. People with DMD are usually in wheelchairs by the age of 10, with most dying before the age of 30.
The exquisite targeting ability of CRISPR/Cas9 editing systems rely on a sequence-specific guide RNA to direct a scissor-like, bacterial enzyme (Cas9) to just the right spot in the genome, where it can be used to cut out, replace, or repair disease-causing mutations. In previous studies in mice and dogs, researchers directly infused CRISPR systems directly into the animals bodies. This “in vivo” approach to gene editing successfully restored production of functional dystrophin proteins, strengthening animals’ muscles within weeks of treatment.
But an important question remained: would CRISPR’s benefits persist over the long term? The answer in a mouse model of DMD appears to be “yes,” according to findings published recently in Nature Medicine by Charles Gersbach, Duke University, Durham, NC, and his colleagues . Specifically, the NIH-funded team found that after mice with DMD received one infusion of a specially designed CRISPR/Cas9 system, the abnormal gene was edited in a way that restored dystrophin production in skeletal and heart muscles for more than a year. What’s more, lasting improvements were seen in the structure of the animals’ muscles throughout the same time period.
As exciting as these results may be, much more research is needed to explore both the safety and the efficacy of in vivo gene editing before it can be tried in humans with DMD. For instance, the researchers found that older mice that received the editing system developed an immune response to the bacterially-derived Cas9 protein. However, this response didn’t prevent the CRISPR/Cas9 system from doing its job or appear to cause any adverse effects. Interestingly, younger animals didn’t show such a response.
It’s worth noting that the immune systems of mice and people often respond quite differently. But the findings do highlight some possible challenges of such treatments, as well as approaches to reduce possible side effects. For instance, the latest findings suggest CRISPR/Cas9 treatment might best be done early in life, before an infant’s immune system is fully developed. Also, if it’s necessary to deliver CRISPR/Cas9 to older individuals, it may be beneficial to suppress the immune system temporarily.
Another concern about CRISPR technology is the potential for damaging, “off-target” edits to other parts of the genome. In the new work, the Duke team found that its CRISPR system made very few “off-target” edits. However, the system did make a surprising number of complex edits to the targeted dystrophin gene, including integration of the viral vector used to deliver Cas9. While those editing “errors” might reduce the efficacy of treatment, researchers said they didn’t appear to affect the health of the mice studied.
It’s important to emphasize that this gene editing research aimed at curing DMD is being done in non-reproductive (somatic) cells, primarily muscle tissue. The NIH does not support the use of gene editing technologies in human embryos or human reproductive (germline) cells, which would change the genetic makeup of future offspring.
As such, the Duke researchers’ CRISPR/Cas9 system is designed to work optimally in a range of muscle and muscle-progenitor cells. Still, they were able to detect editing of the dystrophin-producing gene in the liver, kidney, brain, and other tissues. Importantly, there was no evidence of edits in the germline cells of the mice. The researchers note that their CRISPR system can be reconfigured to limit gene editing to mature muscle cells, although that may reduce the treatment’s efficacy.
It’s truly encouraging to see that CRISPR gene editing may confer lasting benefits in an animal model of DMD, but a great many questions remain before trying this new approach in kids with DMD. But that time is coming—so let’s boldly go forth and get answers to those questions on behalf of all who are affected by this heartbreaking disease.
 Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nelson CE, Wu Y, Gemberling MP, Oliver ML, Waller MA, Bohning JD, Robinson-Hamm JN, Bulaklak K, Castellanos Rivera RM, Collier JH, Asokan A, Gersbach CA. Nat Med. 2019 Feb 18.
Muscular Dystrophy Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Gersbach Lab (Duke University, Durham, NC)
Somatic Cell Genome Editing (Common Fund/NIH)
NIH Support: National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Biomedical Imaging and Bioengineering
Posted on by Dr. Francis Collins
Today, I’d like to share a video that tells the inspirational story of two young Massachusetts Institute of Technology (MIT) researchers who are taking aim at a genetic disease that has touched both of their lives. Called myotonic dystrophy (DM), the disease is the most common form of muscular dystrophy in adults and causes a wide variety of health problems—including muscle wasting and weakness, irregular heartbeats, and profound fatigue.
If you’d like a few more details before or after watching these scientists’ video, here’s their description of their work: “Eric Wang started his lab at MIT in 2013 through receiving an NIH Early Independence Award. Learn about the path that led him to study myotonic dystrophy, a disease that affects his family. Eric’s team of researchers includes Ona McConnell, an avid field hockey goalie who is affected by myotonic dystrophy herself. Determined to make a difference, Eric and Ona hope to inspire others in their efforts to better understand and treat this disease.”