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expert reaction to study looking at CRISPR and muscular dystrophy in mice

Research, published in Nature, reports the use of CRISPR gene editing technique in reversing symptoms of muscular dystrophy in mice.


Prof Dominic Wells, Professor in Translational Medicine, Royal Veterinary College, said:

“The study by Kemaladewi and colleagues is an elegant demonstration in mice of the potential to upregulate a compensatory gene to treat muscular dystrophy.

“They used an inactive form of the Cas9 enzyme and three guide RNAs to specifically target gene activators to the Lama1 gene to upregulate laminin-α1 as a compensation for nonfunctional laminin-α2 in the extracellular matrix, which is one of the causes of muscular dystrophy.  Most importantly, they performed systemic administration of the Cas9, gene activators and guide RNAs using viral vectors in a mouse already severely affected by muscular dystrophy and were able to demonstrate marked reduction in clinical signs and neuromuscular pathology.  This serves as a proof of concept for further development of this approach to therapy for patients affected by congenital muscular dystrophy type 1A (MDC1A) and potentially other muscular dystrophies.

“There are a few limitations that should be mentioned, other than the obvious one that this is work in mice and not yet in people.  Firstly, the study used doses of viral vectors three times higher than the maximum used to date in people.  Secondly, although the abstract suggests that the study showed reversal of muscle fibrosis, it actually only demonstrated prevention of further fibrosis and did not directly compare fibrosis prior to treatment with fibrosis following treatment.”


Dr Alena Pance, Senior Staff Scientist, Wellcome Trust Sanger Institute, said:

“This study in mice presents a development of the well-known genome editing technology based on CRISPR/Cas9.  Instead of using this system to introduce DNA breaks to make modification precise and easier, this strategy uses an inactive enzyme to deliver a transcriptional activator to a precise site of the DNA, to activate a desired gene with the resulting production of a protein.

“The major advance of this approach is the potential to treat complex diseases caused by multiple mutations, maybe even affecting different genes.  Rather than attempting to repair all the defects, if a modifier gene can be found as was shown in this study, its activation can overcome the pathology of the disease.  With this approach, it would be possible to apply the same treatment independent of the particular underlying mutation, which would make any therapeutic approach and potential translation to the clinic much more feasible.  Furthermore, diseases that today escape all possibilities of treatment could finally have a glimmer of hope.

“As this system does not lead to breaks in the DNA, it is deemed safer.  However, the design of the guide RNAs to provide the specific location in the genome follows the same principles as those applied to genome editing, so the potential for off-target effects is still an important issue to consider.  The authors have taken steps to assess this by identifying potential binding sites throughout the mouse genome, concluding that the most important off-target binding sites were unlikely to have an effect.  However, this was done bioinformatically so it remains to be clarified whether there are biological changes occurring as a consequence of the intervention.  The concern stems primarily from the use of a general gene activator, which has the potential to induce expression of any gene to which it is delivered.  Furthermore, the ‘switching on’ of the modifier gene needs to occur in specific tissues – in the case of muscular dystrophy, in skeletal muscles and sciatic nerves.  But the work does not examine its expression in other tissues in the mouse, where expression of this gene could be undesirable.

“Finally, the long term effects of the therapy will also need to be evaluated.  The fact that this strategy does not introduce permanent changes in the genome and the CRISPR/Cas9 will not survive indefinitely in the transduced cells, may be an added advantage of the system because it allows fine tuning of the treatment or indeed the possibility to stop or revert it if necessary.  But it will be important to understand the therapeutic time line to establish any potential clinical protocol that could be applied to humans.”


Dr Kate Adcock, Director of Research and Innovation, Muscular Dystrophy UK, said:

“This is an exciting piece of research, which should give hope to people with congenital muscular dystrophy type 1A and their families.  Targeting disease modifier genes in this way could benefit a wider range of patients, as the technique doesn’t depend on an individual mutation.  It’s also important to note that paralysis and fibrosis were reversed in symptomatic mice, which demonstrates that the technique was still beneficial at an advanced disease stage.

“We’re encouraged that the technique did not appear to cause unwanted gene editing, but there is still a way to go before any treatment is brought to clinic.  The next step will be to replicate the study in other animal models before we extend the study to humans.  This may not be a cure, but it’s a step in the right direction to finding a treatment for congenital muscular dystrophy type 1A.”


* ‘A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene’ by Dwi U. Kemaladewi et al. was published in Nature at 18:00 UK time on Wednesday 24 July 2019. 

DOI: 10.1038/s41586-019-1430-x


Declared interests

Prof Dominic Wells: “I work on developing and testing treatments for neuromuscular disorders and particularly for Duchenne muscular dystrophy.  I have no ongoing work similar to this piece of research.”

Dr Alena Pance: “I, Alena Pance, declare I do not have any conflict of interest with regards to this work.”

Dr Kate Adcock: “No conflicts of interest.”


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