Webinar Q&A: Gene Therapy Part 2 – Nationwide Children's Hospital

This fall, PPMD is presenting a gene therapy webinar series with companies and institutions who are developing therapies for Duchenne that are commonly referred to as gene therapy, including micro-dystrophin and CRISPR/Cas9.


The second webinar in this series took place on Wednesday, September 6 at 2 PM ET, featuring Dr. Jerry Mendell of Nationwide Children’s Hospital who discussed his upcoming gene therapy trial, including trial design, inclusion/exclusion criteria, and timelines.

Webinar Recording

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.


  1. Why is exon 12 not eligible?
    If we express the micro-dystrophin gene (which contains exon 12) when exon 12 is missing we could get an immune response following gene delivery that could jeopardize benefit.  

  2. Is Exon 70 eligible?
    Exon 70 is not eligible for the same reason as exon 12, ie if we express the micro-dystrophin gene (which contains exon 70)  when exon 70 is missing we could get an immune response.

  3. What about boys who are outside the exon range of 18-58... like a stop codon at exon 11?
    This again will favor developing an immune response because the stop codon in exon 11 will not express beyond the mutation predisposing the non-expressing part of the gene from exon 12 to 17 vulnerable for developing an immune response.  

  4. My son is 2 years old and has a mutation on exon 9. When do they think trials for those exons begin?  
    We believe that if we are effective in our first clinical trial we can petition the FDA to let us treat patients outside the permitted exon range of 18-58. It is difficult before the trial to provide a specific answer in terms of months but we are optimistic that this will be in time to help boys as young as 2 years of age.

  5. My son was diagnosed this year at 8 years old and he has nonsense mutation and intermediate muscular dystrophy. Will you be accepting patients from Canada?
    We would be excited to treat 8 year olds with nonsense mutation and an intermediate clinical picture because it means that their milder clinical course indicates that more muscle is remaining. More muscle for gene delivery predicts a better outcome.  Treating a boy at this age with this clinical picture will require another request to the FDA because the current upper age limit for the trial is 7. We are also receptive to treating boys from Canada.

  6. Would gene therapy also work for a nonsense mutation that results in a pre-mature stop in exon 30?
    Based on experimental work in mdx mice that have a stop codon in exon23, we believe that gene delivery will work in patients with a stop codon in exon 30.  We plan on treating DMD boys with stop codons if their mutation is between exons 18-58. 


  1. What is worst case scenario?
    The worse-case scenario, in any trial, is loss of life or a serious life-threatening adverse event.  
  2. What is best case scenario?
    The best-case scenario is that we show by one year after gene transfer that the distance walked on the 100m walk test reaches 90% predicted.  In our study of the 100m walk test in boys with DMD, no boys at any age could reach this level of performance. For the young cohort participating in this trial, a one-point improvement on the Bailey-III for 5 of the 6 participants would be a clear indication of efficacy.
  3. How are trial participants chosen? Are they sought out or do they need to find you?
    We have multiple routes of study entry. When the trial criteria for entry are established (as they are for this study) we look for DMD patients in our own muscular dystrophy clinic at Nationwide Children’s Hospital who meet enrollment criteria.  We also send out notifications to the Directors of PPMD Certified Duchenne Care Centers (16 Centers certified by PPMD providing comprehensive care for DMD) notifying them that we are enrolling patients and informing them of the criteria for enrollment. The same information is provided on the Nationwide Children’s Hospital website under the Center for Gene Therapy.  For patients who directly contact our Center through email correspondence or by telephone we try and arrange teleconferences with our Research Nurse Specialist and a Study Coordinator to try and get all of the essential information necessary for trial enrollment.
  4. Would my son's participation in a myostatin inhibition study exclude him from this study? 
    If the myostatin study was delivered through gene delivery they would not be candidates. If this was an antibody study or a drug that blocked the myostatin pathway, they could be candidates after a 6 month wash out.
  5. In this first trial, there will be 12 boys total, 6 from each age cohort? Am I understanding that correctly? 
    It is our intent to enroll 12 boys in two different age groups (4yo-7yo and 3 months old to 3 years old), with 6 in each age group.
  6. What is the numeric difference between the clinical dose and highest dose?
    We intend to start the trial at a dose of virus carrying the gene at 2X1014vg/kg that we designate therapeutic because we had very good results in experimental animals. We are leaving the option open for potentially moving to a higher dose if we have no response at the therapeutic dose. The high dose is 6X1014vg/kg of virus carrying the gene.
  7. How different is this trial from the trial that happened in France on Dogs?
    The study design in the canine model for DMD conducted by the French in collaboration with University of London is very similar to the strategy we are using in the patient trial we have planned. Their study in a large animal model and its benefit are very promising and provide further credibility and hope for our approach.
  8. If this trial is shown to work as expected is it necessary to have a placebo based trial?
    This is always a challenging question. Whenever possible we prefer for first in-human clinical trials not to do placebo-controlled trials to avoid the need for multiple biopsies and blood draws required to match the treated group. We are also concerned about missing the opportunity to treat the patient at the earliest possible time to achieve the best possible results. However, placebo-controlled trials are often considered more definitive and the sponsoring foundation or the NIH often prefer inclusion of a placebo group. To answer the question more directly, if the trial is convincingly successful it is likely that the findings will be accepted for consideration of what the FDA describes as Accelerated Approval but before the gene can be accepted as definitive treatment, the study will have to be done in a multi-clinic setting and may require a placebo group.
  9. Is cardiac function being assessed?  
    The heart is critically affected in DMD and the goal of our clinical trial is to improve cardiac function.  It will be checked repeatedly during this trial. We have designed the gene we are delivering to be expressing well in the heart and have seen proof of this in all of our experimental studies in preparation for the clinical trial.
  10. Why are older non-ambulatory patients not included?
    It is more difficult and takes longer when boys are not walking to make sure the treatment is beneficial.  For that reason, improvement in ambulatory boys permits us to extend the trial to a large cohort of non-ambulatory patients more rapidly.
  11. Can MRI and MRS be useful in comparing muscle architecture?
    The technology of MRI and MRS has rapidly expanded and these two modalities confirm findings that we see at a clinical level. With these findings of improvement by MRI and MRS the success of the trial will be better accepted.
  12. How long is the trial?
    The full length of the trial is three years inclusive of safety and full testing of how long the gene will work. Often if the gene works short-term this will not be satisfactory and we and the FDA are interested to know if the effect will persist for three years. With three year results the trial findings are better accepted. 


  1. How would a placebo trial work when the boys build up antibodies to the AAV virus. Would they not get the virus?
    During the trial we monitor antibody levels to the virus. If the antibody levels rise to high levels we would consider suppressing the antibody with corticosteroids (prednisone or prednisolone). If the trial is placebo-controlled, antibodies would not build up in these patients. We have potential ways of delivering the gene in the presence of antibodies and if it was present in the treated patients this would not deter us from treating the placebo cohort.
  2. Can NAB (Neutralizing Anti Body) profiling help in increasing the spectrum of gene therapy, so immune response to primary humoral response can be considered controlled?  
    Neutralizing antibodies to AAV are checked before enrollment. The FDA has set guidelines for the level of NAB permissible for enrollment.  The profiling itself cannot increase the number or the spectrum of patients to be enrolled. Only removing the antibody from the blood of individuals showing high titers can make gene therapy available to those patients with pre-existing antibodies prior to clinical trial.



  1. How many times will gene transfer be required?
    Gene transfer is done only one-time. This is an attribute greatly overshadowing any type of drug therapy or oligonucleotide treatment for gene modification (like exon skipping).
  2. Is it easier to repair deletions over other mutations?
    It is not necessarily easier to repair deletions. Point mutations with stop codons and point mutations that are not stop codons (missense mutations) are likely to be more receptive to gene replacement therapy.  The muscle is better preserved and the clinical effect milder with point mutations. This means more muscle is available for gene replacement with better outcomes.  Missense mutations that only slightly change the dystrophin protein are less likely to have an immune response with gene replacement.
  3. Can you please explain whether muscle cell division will 'dilute' the effect of the microdystrophin?
    It is not muscle cell division that dilutes the effect of gene replacement.  The long-term efficacy will depend on how many nuclei of the muscle fiber are the recipient of the gene when it is replaced. The more that receive the gene, the more secure the long-term treatment will be.  To understand this it is important to appreciate that muscle cells do not divide but there are multiple nuclei in each muscle fiber. If a nucleus does not receive the gene at the time of gene transfer then that area of the muscle fiber assigned to that nucleus is not protected. It could then undergo degeneration. When this happens the muscle regenerates in that area but without the gene that we delivered at an earlier time. If very few nuclei of the muscle fiber receive the gene at the time of gene transfer more and more segments of the muscle fiber degenerate and over time the entire muscle fiber is lost. If this happens over and over again, there is no benefit to gene therapy.
  4. Is this Gene Therapy effective for Limb Girdle Muscular Dystrophy?
    We are testing gene therapy in limb girdle muscular dystrophy just like in DMD and the results are not yet available. 


  1. What's your opinion regarding other microdystrophin attempts like Solid's SGT001?
    The proposed study by Solid looks promising and the gene for delivery is similar to ours. It appears from any public statement they have shared that their clinical trial will begin after ours and their strategy for enrollment also appears to be different.  Given that they are a private company any further information will have to be released by Solid.

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