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Traditional gene therapy and emerging gene editing therapy for Duchenne Muscular Dystrophy (DMD), which one is better? Some recent research may give us some new thinking.

 

There are approximately 300,000 DMD patients worldwide. Due to the presence of mutations, patients are unable to produce dystrophin normally, causing atrophy of skeletal muscle and myocardium. Patients are often unable to walk and die of heart failure in their twenties.

 

Several companies, including Sarepta, Solid Biosciences, and Pfizer, have research and development programs for gene therapy for DMD. At present, Sarepta is not only progressing, but from the data published two months ago, the company’s treatment (rAAVrh.74.MHCK7) also has certain advantages.

 

However, this week’s new article in Science has used a new way to treat DMD: the researchers used the CRISPR-Cas9 gene editing system to treat four beagle dogs.

 

Approximately 13% of children with DMD have mutations in the exon 45-50 range, causing abnormalities in exon 51 and interfering with the normal transcriptional process of the gene, rendering the patient unable to produce normal dystrophin.

 

In 2009, a laboratory at the Royal Veterinary College in the United Kingdom found a Spanish hound with an exon 50 deletion mutation and affected the normal function of exon 51. The Beagle offspring based on this dog was also used as an animal model for Duchenne muscular dystrophy.

 

In this study, the researchers used CRISPR to cleave the front end of exon 51 to create an indel by non-homologous recombination to cause exon skipping in the DNA transcription system, resulting in a shortened but functional muscle. Atrophin (the marketed DMD drug eteplirsen is based on the mechanism of exon skipping, but the efficacy of this drug is still controversial).

 

Another difficulty in gene therapy treatment is the delivery of drugs, and editing billions of muscle cells in the body at the same time is not an easy task. The study successfully used the AAV vector, which selectively infects muscle and myocardial tissue, to successfully complete the systemic delivery of the drug. The study is also the first published study to complete systematic delivery of CRISPR in large mammals.

 

The results of the study showed that the therapy can significantly increase the expression of dystrophin in muscle tissue, such as the diaphragm and heart expression levels reached 58% and 92% of normal levels, respectively. However, because the animal was euthanized, the study did not find out whether the therapy can alleviate the symptoms of DMD in experimental animals.

The traditional gene therapy strategy for treating DMD is significantly different from the above strategy. Since the dystrophin gene is the largest gene in the human body, it is difficult to load using a viral vector. So Solid Biosciences and Serapta use viral vectors to load a reduced version of the smallest gene that expresses dystrophin.

 

Serapta’s clinical trials have shown that in a study involving three younger patients, their gene therapy boosted dystrophin levels to 38% of normal levels. And in a clinical trial at Solid Biosciences, a 14-year-old boy also developed symptoms.

 

But whether it’s Solid Biosciences, Serapta, and Pfizer’s traditional gene therapy, or the CRISPR-based gene editing therapy reported by Science, the data for these studies are at an early stage and it is difficult to make direct comparisons. But no matter which type of therapy is a new hope for patients.

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