Amoasii L, Hildyard JCW, Li H, et al. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science (New York, N.Y.) 2018;362:86-90.
The first experiment of CRIPSR/Cas9 gene editing of the dystrophin gene in a canine model. The results were promising; however it is only one dog for a very short period, so no real conclusions can be drawn. No therapeutic effect was seen over this short period.
It must be clear that gene editing is no cure, since if effective, still no fully functional dystrophin protein will be formed. Furthermore, there are concerns regarding the specificity of the technique (side effects), which have to be investigated carefully.
Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.
Including a commentary article, discussing the promises and limitations of the results retrieved.
Wasala NB, Hakim C, Chen SJ, Yang NN, Duan D. Questions answered and unanswered by the first CRISPR editing study in the canine model of Duchenne muscular dystrophy. Human gene therapy 2019.
CRISPR editing is being considered as a potential gene repair therapy to treat Duchenne muscular dystrophy (DMD), a dystrophin-deficient lethal muscle disease affecting all muscles in the body. A recent preliminary study from the Olson laboratory (Amoasii et al. 2018 Science 362:89-91) showed robust dystrophin restoration in a canine DMD model following intramuscular or intravenous delivery of the CRISPR editing machinery by adeno-associated virus serotype-9 (AAV9). Despite the limitation of the small sample size, short study duration and the lack of muscle function data, the Olson lab findings have provided important proof-of-principle for scaling up the CRISPR therapy from rodents to large mammals. Future large-scale, long-term, and comprehensive studies are warranted to establish the safety and efficacy of CRISPR editing therapy in large mammals.