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Potential for Genome Editing in Neuromuscular Disease

Over the last year, the Myotonic Dystrophy Foundation has carefully examined the potential of genome editing strategies to address myotonic dystrophy, including hosting an expert workshop and a competition for research grant funding. In these efforts, the focus has been upon the need to evaluate various genome editing strategies, optimize reagents, identify an effective delivery vehicle, and establish systems to assess both safety and efficacy in preclinical models—as reported out from the workshop. Although genome editing is rapidly moving into the clinic for other disease indications, the technology likely is not yet optimized and the DM field will benefit from learnings from any first-in-man studies.

Progress in Genome Editing for Neuromuscular Diseases

Haris Babačić (now a Ph.D. student in proteogenomics at Karolinska Institute), Dr. Benedikt Schoser (Ludwig-Maximilians-University of Munich), and colleagues have conducted an intensive analysis of preclinical research publications in neuromuscular and repeat expansion disorders to ascertain key lessons for moving genome editing strategies forward. Their review was recently published in PLoS One (Babačić et al., 2019). Their review provides important perspectives obtained from one genome editing platform, CRISPR-Cas, so that learnings are not siloed within disease fields.

These authors utilized literature searches of MEDLINE and EMBASE databases (coverage up to the end of 2017) to identify publications focused on use of CRISPR-Cas genome editing systems in preclinical studies of at least one monogenic neuromuscular disease. In all, forty-two publications met all eligibility criteria and were reviewed. Like the MDF Genome Editing Workshop, this publication identified the efficient delivery of editing reagents and evaluation of their safety and efficacy as the salient issues in moving toward clinical testing of this therapeutic strategy.

The majority of studies reviewed here (n = 26) were in preclinical models of Duchenne muscular dystrophy (DMD); information was also obtained from publications in Huntington Disease (HD; 5 publications), Spinocerebellar Ataxia 2 (SCA2; 3 publications), Friedreich’s ataxia (FA; 1 publication), myotonic dystrophy type 1 (DM1; 3 publications), Fragile X syndrome (FXS; 2 publications), and three other types of muscular dystrophy (FSHD, MDC1A, and LGMD; 1 publication each).

Lessons from Studies of Genome Editing

The theme that the efficacy of genome editing is influenced by selection and delivery of guide RNAs (gRNA) and Cas was readily apparent among the publications focusing on DMD. Efficacy was shown for DMD in in vitro, ex vivo, and in vivo models. Delivery predominantly relied upon viral vectors, although use of gold nanoparticles has shown potential. Evaluation of the specificity of off-target editing (safety) largely focused on sequences predicted using bioinformatic models—an approach unlikely to be sufficient to support clinical development (as per the NIST Genome Editing Consortium).

Studies in DM may need to overcome difficulties in removal of the long, expanded repeat tracts; yet a strategy of targeting and eliminating the toxic repeat RNA with dCas9 has also been tested. The review’s authors note that mRNA targeting would require life-long administration of the candidate therapeutic—potential consequences of that strategy are not yet known, although there is a more general concern about off-target and immunological consequences of continues expression of the Cas protein. These safety concerns may require use of a delivery system in which Cas protein can be switched off after editing is complete.

Analysis of the other indications addressed in this review led to few additional lessons, outside of therapeutic window considerations that are disease-specific. The authors do include an important section on ethical issues that accompany genome wide editing strategies, ranging from benefit-risk assessments to the societal issues raised by germline editing. Overall, the review’s authors acknowledge the rapid progress that has been made in moving a potentially game-changing therapeutic forward, but conclude that the evidence to move into clinical trials for neuromuscular diseases is insufficient. They argue for more basic research to optimize delivery systems, thoroughly assess off-target safety concerns, and create standards for efficacy determination before transitioning to clinical trials. These are goals that are consistent with the due diligence that MDF has done to assess the opportunities and challenges of using genome editing in DM.


CRISPR-cas gene-editing as plausible treatment of neuromuscular and nucleotide-repeat-expansion diseases: A systematic review.
Babačić H, Mehta A, Merkel O, Schoser B.
PLoS One. 2019 Feb 22;14(2):e0212198. doi: 10.1371/journal.pone.0212198. eCollection 2019.





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