CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy: Prime time already?

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December 12, 2018 – The application of CRISPR/Cas9 based molecular technology in the field of gene editing (or genome editing) has recently had its exploded limelight exposure for a couple of reasons. The question arises if this exposure is earned or somewhat premature.

First of all, there was the very recent announcement by a Chinese scientist about the creation the world’s first genetically edited babies, in a potentially ground-breaking and controversial medical first. The scientist claimed that he altered embryos with the intention of curing or preventing an inherited disease, but rather trying to bestow a trait that few people naturally have: the ability to resist possible future infection with HIV. This would be a profound leap in medical sciences and, most of all, in human ethics in that for the first time embryos have been gene edited for gaining a function humans normally do not have, and not for the remedy of a preexisting condition of disease. In particular, in the present case, the scientist chose embryo gene editing for HIV because these infections are still a major health problem worldwide. He sought to disable a gene called CCR5 that forms a protein doorway that allows HIV, the virus that causes Aids, to enter cells and therefore infecting people.

Second, early embryos have previously been gene edited by the CRISPR/Cas9 method  in oder to repair the mutated MYBPC3 gene which is thought to be the pathogenic key to hypertrophic cardiomyopathy (HCM) which is the most common cause of sudden cardiac death in otherwise healthy young athletes, and affects approximately 1 in 500 people overall. But this study stopped at that level, and did not led to a implantation and growing the embryos to gene edited babies as the new Chinese study did. It only showed that it was possible to create  early embryos that were carriers of a corrected functional MYBCP3 gene. Thasso post published on the topic in the past.

Lastly, some of the hype about CRISPR/Cas9 stems from the fact that there are a number of clinical trials under way, which explore the clinical applicability of CRISPR/Cas9 for different scenarios from correction of inherited disease to oncology. You can easily check for planned, ongoing, or completed clinical trails with CRISPR/Cas9 at and searching for CRISPR/Cas9.

However, within the euphoric surrounding CRISPR/Cas9, one serious aspect has been forgotten: Potential unforeseen side-effects of the CRISPR/Cas9 technique are going to be stably introduced into the genomes of early or late embryos or children born after gene editing and are therefore going to be passed on from them to future generations.

A recent study by  Lim et al., just published in the Journal of Personalized Medicine (J. Pers. Med.) on November 24, 2018, has addressed some of these issues by using ongoing CRISPR/Cas9-related in vitro and in vivo studies and activities around Duchenne muscular dystrophy (DMD). DMD is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. As an RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. Because of this constellation of a single gene in the etiology of a disease, DMD offers itself as a prime target for the exploration of the promises of CRISPR/Cas9 techniques as a therapeutic approach. Thus, the efficacy and safety of CRISPR/Cas9 as a therapy for DMD has to date been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently still challenged by unsolved safety issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. All of these events, which may and do occur both, in cellular systems in vitro and in animal model systems of DMD in vivoillustrate the potential of the CRISPR/Cas9 technique to introduce novel, genetically fixed sequelae into the population, should they also occurring in the CRISPR/Cas9 based gene editing of human embryos. Moreover, on the single individuals patients bast, the nature of CRISPR/Cas9 as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations.

In conclusion, based on current knowledge gained from  an ongoing  “ideal” model case of a serious human disease such as DMD so far, CRISPR/Cas9 based therapy approaches are not yet ready for prime time, and the application in the clinic poses still some serious safety questions, surely for individual patients, and even more so when applied to gene editing in early embryos who may transform into babies and constitute the basis for “gene edited” future generations. As such, the experimentations of the Chinese scientist are, at current time, simply irresponsible from an ethical point of view.

By the way, the article by Lim et. al. is just one of several in the outstanding special issue on  “Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases” in the Journal of Personalized Medicine (J. Pers. Med.), a must read Journal for anyone, from researcher to physician and patient alike, concerned with all aspects of personalized and theragenomic medicine. See also here the full text of the study by Lim. et al. (Full-Text).

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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