PPMD Is Seizing This Moment to Explore the Potential of CRISPR/Cas9 in Duchenne

It is the holidays – time for giving and laughter and hope. Hope comes in many forms, but I would imagine that for many reading this blog, hope comes in the form of a cure for Duchenne.  

Could CRISPR/Cas9 offer hope for treating Duchenne? 

As background, CRISPR/Cas9 is a method that allows scientists to find very specific targets within DNA, or our genetic code, and make specific cuts or changes to the DNA. Because these changes are made at the DNA level, they are more permanent than not.

One potential use with CRISPR/Cas9 is to actually cut out or skip over an exon just like is done in exon skipping therapy with antisense oligonucleotides. Just as in traditional exon skipping, the body would make a functional but shortened dystrophin protein. 


CRISPR/Cas9 holds so much hope, but as with any new technology there are still many complex questions that must be answered as best we can, before it is ready to be tested in humans.   

How do we find out if CRISPR/Cas9 holds promise in Duchenne? 

A human clinical trial is just that, a trial, to see if a therapy offers benefit compared to the risks it poses. And understanding the benefits and risks as much as we can upfront is what researchers are doing now to get CRISPR ready for the clinic.

PPMD is working with researchers to better understand the potential of CRISPR/Cas9 technology in Duchenne, including Dr. Eric Olson, from the Department of Molecular Biology at UT Southwestern Medical Center.

Dr. Olson and his team are seeking to answer a couple of these questions in preparation for entering into clinical trials.

1. How stable is this dystrophin protein produced by CRISPR/Cas9?

The first question we are asking Dr. Olson to further research is how stable is the dystrophin protein that is made from CRISPR/Cas9? And how do the different types of shortened dystrophin protein function and compare to each other? Are some more stable and more functional?   


Dr. Olson’s lab will study the various types of dystrophin proteins produced using CRISPR/Cas9 in mouse models. In addition, they will also compare the dystrophin proteins produced from CRISPR/Cas9 to proteins produced from other therapeutic approaches, such as the micro dystrophins being researched for use in gene transfer. 

2. What are the safety risks?

The second question we are asking Dr. Olson to look into is whether there are any unwanted “off-target” effects.  CRISPR/Cas9 works as a pointer through its “RNA guidewires”, directing the CRISPR to the exact area of the genetic code where it needs to go. What we don’t know is how often the system finds an area that is close but not exact yet still ends up cutting the genetic code there. This unintentional cut could lead to what is considered “off target” effects. 


Dr. Olsen’s lab will study the potential for any deleterious off target effects using a variety of methods.  First, off target effects will be examined by sequencing predicted sites and by whole exome sequencing the mice injected with CRISPR/Cas9 to look for any effects in the not predicted places.  He will also study the biodistribution (where the drug travels to in the body) of CRISPR/Cas9 in mice by examining many types of tissues six months post treatment in biodistribution studies.


Because CRISPR/Cas9 delivery relies on AAV9, the safety of this delivery method will also be examined, including looking for any immune response to the AAV9 and any integration issues. This in depth look at the safety will help us more comprehensively characterize any risks associated with CRISPR/Cas9.


These studies will help plan the toxicology studies that need to be done as part of the IND (Investigational New Drug) Application that the FDA must approve to be able to go into clinical trials. 


The time is now


We all live our lives with purpose every day – and part of that purpose is shaped by hope. What do we hope for? What do we dream of?


As Pat has said, there will not be one ‘silver bullet’ that stops Duchenne. We believe in strongly in a combination of therapies that will attack Duchenne from every angle. We hope that CRISPR/Cas9 is a part of that combination. But we won’t know what potential CRISPR/Cas9 has in treating Duchenne without these trials. For PPMD, it’s about seizing this moment and learning everything we can in the hopes that it will lead closer to the day we end Duchenne.


“The question is whether or not you choose to disturb the world around you, or if you choose to let it go on as if you had never arrived.” - Ann Patchett, writer (b. 2 Dec 1963)


Upcoming Webinar: A Closer Look at the Potential of CRISPR/Cas9 in Duchenne

Join PPMD Thursday, December 15 at 2:00 PM ET for our second webinar on this exciting technology. PPMD again welcomes Dr. Eric Olson from the Department of Molecular Biology at UT Southwestern Medical Center to review the basics of gene editing and talk about some of the next steps in the research and development pathway.


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