Webinar Q&A: Gene Therapy for Duchenne

With trials in gene therapy on the horizon, and terms like "cassette", "construct", "promoter", and "transduce" being thrown around, we want to ensure that you, our Duchenne Community, has all the knowledge you need to navigate the world of gene therapy.

Earlier this month, PPMD hosted a webinar with Lee Sweeney, PhD (University of Florida) and Melissa Spencer, PhD (UCLA) focused on understanding the different therapies that are being developed that are commonly referred to as gene therapy, including micro-dystrophin and CRISPR/Cas9, how are they similar and different, and what are the challenges and limitations for each of them. If you missed it, the recording is now available below.

COMING SOON: This fall PPMD will be hosting additional webinars with companies and institutions who are developing gene therapies and/or CRISPR/Cas9 for Duchenne. Stay tuned for more details!

Webinar Recording

Download PDF

Additional Questions

There were some great questions asked, but unfortunately we were not able to get to all of them during the webinar. The remaining questions have been addressed below.



  • Will these new vehicles of delivery (vectors/capsids) also have to go through an entire clinical trial process? Curious how this plays into the timeline. 
    • The new vectors containing the microdystrophins will be treated from a clinical development perspective like any other product and will have to be proven to provide more benefit than known risk. The capsids themselves do not add anything to the clinical trial process. Even though the virus itself has been in trials, everytime the transgene in the virus changes, there must be new toxicology (preclinical work in animals looking at safety) work as well as a new human trial.
  • Is there some sort of timeline when some of this stuff will be available? 3 years? 5 years? 10 years? We just want to be realistic with our hope.a.    
    • There are many unknowns that play into accurately answering this question. Once a trial starts in humans it can take as long as 2 – 10 years depending on what happens.  A realistic timeline for approval would be 5-7 years, if all goes exceedingly well.
  • When are all the for Microdystrophin starting?
    • The trials will most likely start sometime in 2018. This is all dependent on each company’s interactions with the FDA and when they have completed and submitted the necessary elements that the FDA requires to start a first-in-man trial. 


  • Which exons specifically are considered "critical" for function?
    • The actin binding region (at the beginning of the protein), the dystroglycan binding region (near the end  of the protein), and 4 or 5 of the spectrin-like repeats seem to be the most critical components. More spectrin-like repeats would be better, but AAV cannot fit all of them.
  • It seems like out-of-frame deletions are critical for cellular acceptance.  Does Microdystrophin have a bit of an advantage for avoiding hinge issues?
    • If the deletion is in-frame, then technically the person has BMD instead of DMD. But a microdystrophin will rescue any type of mutation. The only issue is if the patient’s deletion covers a region that is present in the micro-dystrophin, then there is the theoretical possibility of an immune response. 


  • Also for the 20% of boys who will not be eligible for gene therapy due to an immune response to the current vector/ capsid? What is the plan for this? 
    • First, the number is likely to be lower than this since the 20% number is based on adults. There are ways of getting around this that have been successful in animals. If AAV gene therapy works in DMD pateints, then these techniques will likely be used to try to get around the problem.
  • Can you speak to the timeline for new vectors/capsids that will need to be used for gene therapy "re-dosing"?
    • Just as with natural exposure to the virus,  ways of getting around the redosing problem have been successful in animals. If AAV gene therapy works in DMD patients, then these techniques will likely be used to try to get around the problem. If they don’t work in people then new serotypes may be used. There are a number of possible candidates but the timeline for developing them will not be clear until there is a need for them.
  • Can the AAV vector be used only once in the treatment of DMD during one's lifetime?
    • For the reasons given in #2, it is likely that we will be able to develop a re-administration strategy.
  • In case my son is treated with micro dystrophin, would he be able to be treated by Crispr Cas in the future? Since both use AAV, would that limit the patient to choose one kind of treatment or other?
    • Again, for the reasons given in #2, it is likely that we will be able to develop a re-administration strategy for AAV that would allow the use of CRISPR/Cas. But at the moment, microdystrophin administration will likely produce better results in patients. If someday AAV delivery to satellite cells is made efficient, and issues with Cas immunogenicity are dealt with, then CRISPR/Cas may offer an advantage.
  • Say you start micro-dystrophin and you are in that trial, but then CRISPR-9 gets going and a trial is out for that, what happens with the AAV, especially if both trials are using the same AAV, what does the patient do?
    • This is not likely to happen anytime soon. AAV- CRISPR/Cas has a lot of issues to be overcome before it can go into DMD patients. Besides, the microdystrophin treatment is likely superior to the current implementation of CRISPR/Cas in DMD. 


  • Dr. Mendell's trial is excluding early mutations. Does Bamboo and Solid Bio intend to include all exons? 
    • Until Bamboo and Solid Bio receive feedback from the FDA and choose to disclose their protocol design, we don’t know.
  • For the upcoming trials, what range of exons will be considered? There was buzz around the conference that the earlier exons (1-12) and later exons would not be considered for the trials. 
    • There are three trials anticipated to start within a year. One, Dr. Jerry Mendell Nationwide Children’s Hospital, will only include frameshift mutations between exons 18 and 58. We do not know what the inclusion criteria of the other trials yet.
  • With a deletion from exon 63 all the way to the end, GT is the way to go, no other for what we've being told, so now what's next for us to do?
    • While early stage trials in Gene therapy may exclude certain mutations, the intent for a treatment is to include all mutations. So while you may not be able to participate in these early Phase 1 safety trials, you may be able to participate in other later studies and be eligible for treatment. We are just embarking on this research in humans and it will take these first studies to learn what comes next.
  • We keep hearing that things like gene therapy and cripsr will be effective with about 80% of mutations....I just want to know what those mutations are and if my son's mutation would be amenable to these types of therapies potentially in the future. He 16 months old, and didn't make the qualifications for Dr. Mendel’s upcoming clinical trial because of his mutation. He has a deletion of 57-59.
    • Micro-dystrophin can be effective in 100% of the patients if there is not an immune response. Your son likely will be eligible for one of the other planned micro-dystrophin trials or a later phase 2 trial. CRISPR/Cas has great long-term potential, but it likely will be less effective than micro-dystrophin for most patients if the current technology is used. Your son would need exon 56 to be skipped, which could result in a highly functional protein if CRISPR/Cas can someday be used.
  • The Nationwide trial will include those with frameshift mutation between exons 18 and 58. What about a mutation in exon 58? How do you tell where the boundary is between exon 57 and 58?
    • A mutation in exon 58 would be eligible for the Nationwide trial.
  • My son has a duplication of Exon 6.  Could duplications be deleted and therefore the code would still fit? Or, would deleting, say 53, delete both of his 53s.  In other words, is there a way to delete the copied exons while leaving the first one in the code?
    • It might be possible to design a strategy to delete only one copy of your son’s exon 6. But this would not be a general strategy and would have to be designed specifically for your son, a la personalized medicine. The regulatory pathway for personalized medicines has not yet been forged. Your best option is to enroll your son in a micro-dystrophin trial that does not exclude early mutations.
  • What about treating Duplications?
    • See question above.
  • Could AAV work for patients with inframe mutations (severe BMD?)
    • Micro-dystrophin can be effective in 100% of the patients, including in-frame deletions (BMD).
  • Any microgene transfer trials for exon 12 that is starting?
    • There are three trials being planned. The Nationwide trial would not include an exon 12 mutation. We do not know what the Bamboo and Solid Bio trials will include. 


  • Any idea how many children would be accepted in the trial program next year?
    • The Nationwide trial is tentatively planned to include 9 patients – 6 treatment and 3 placebo. We do not know how many the Bamboo and Solid Bio trials will include
  • Does the trial accept patient from Canada?
    • Unknown until listed on clintrials.gov. Most likely phase 1 safety studies will not include international patients.
  • Is the trial international?
    • Unknown until listed on clintrials.gov. Most likely phase 1 safety studies will not include international patients.
  • Can Duchenne boys participate in this trial from Iran?
    • Unknown until listed on clintrials.gov. Most likely phase 1 safety studies will not include international patients.


  • My question is, which of these therapies (if any) can address the cognitive effects of low dystrophin in the brain?
    • The current micro-dystrophin expressing AAVs will not express in the brain. They are restricted to heart and skeletal muscle. Even if they did express in the brain, we do not know if the cognitive defect can be corrected. 


  • I'm also curious about crispr; as from what I understand it sounds similar to an exon skipping type therapy where it cuts out the bad to join the good? Would that be an accurate/super-simplified idea of crispr?
    • That is an accurate super simplified idea of CRISPR as it is being currently pursued. It turns a DMD mutation into a BMD mutation. Whether it is mild or severe BMD will be dependent on the specific mutation.
  • Will CRISPR work for rare mutations?  
    • Theoretically, yes. It is being currently developed as an exon skipping methodology, so as in exon skipping with oligonucleotides, the more common mutations will be tested first. But micro-dystrophion will work for all mutations and is going into trial now, unlike CRISPR.
  • Would CRISPR be effective in BMD patients?
    • The goal of CRISPR, as currently proposed, is to create BMD. A BMD patient should use the micro-dystrophin therapy.
  • I had been reading up on the research with Dr. Duan going on in Missouri. What about the use of CRISPR-CPF1 over CRISPR-CAS9 for better pinpoint delivery?
    • The point is to create less potential for off-target effects. There are other issues as well.
  • So CRISPR and Exon Skipping will in effect, have potentially similar outcomes in that you create a truncated protein that puts the protein back in frame? Does making the changes to the DNA potentially have more impact/efficacy than making changes to the RNA (Exon Skipping)? 
    • Changing the DNA leads to a longer effect and may be more efficient.
  • Which one works better, CRISPR or Gene Transfer, with a duplication at the exon 5 or 6?
    • If by gene transfer you mean gene transfer using micro-dystrophin, then as currently proposed, micro-dystrophin is likely to work better for all patients than will CRISPR/Cas. It is a therapy that will soon be in the clinic. CRISPR/Cas has too many issues to be in the clinic soon and it needs further development before it can compete with AAV-micro-dystrophin.



  • Will older Duchenne patients be able to benefit from this treatment?
    • It is unknown at this time how much benefit older boys will experience and is most likely to be very patient specific.

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