DMD research

PPMD Conference Update: Blog 1: Gene therapy for DMD/BMD

Blog 1: Gene therapy for DMD/BMD

by Alex Johnson, Co-founder and Co-CEO of Duchenne UK

2nd July 2018

Following exciting preliminary results from the Nationwide/Sarepta’s micro-dystrophin gene therapy clinical trial the Duchenne community gathered in Arizona to learn more about the latest developments. Following lots of questions I have received recently I wanted to share with you the notes I took during the presentations.

It’s important to stress that these are early days and lots of questions remain around durability (how long it will stay working in the patients), doses, expanding to young and adults and there are significant challenges with manufacturing that need to be overcome. I have left Arizona with hope that these challenges can be overcome in time but I believe it can be done faster if all the companies, clinicians, researchers and charities come together to address them. We simply don’t have time for people to work in silos to address these challenges that stop us bring effective treatments to our community.  

There are currently no Duchenne gene therapy clinical trials running in the UK but when we met with all three companies they expressed a desire to open trial sites in the UK in the future. We will continue to work with all the companies to try and turn this into a reality through our work on the DMD HUB as quickly as possible.


The Different Gene Therapy Approaches

The goal of gene therapy is to develop methods to replace or repair the dystrophin gene.

Gene Replacement: AAV/micro dystrophin.

Micro-dystrophins can be delivered round the body giving access to to skeletal and cardiac muscle with AAV viruses, one treatment could potentially last for years (durability is still unknown). If there are issues with patients having pre-existing anti-bodies to the virus being used to deliver the gene, I found it encouraging to hear researchers and clinicians are working on strategies are currently to overcome these issues by using things like Plasmapheresis which could mean this could be a treatment for all. It’s important to remember Micro-dystrophins are about one third of the size of a full protein therefore hopefully creating a Becker like disease. It is not a cure.

Gene replacement with micro-dystrophins are being systemically dosed in human clinical trials with three companies; Solid Biosciences, Jerry Mendell/ Sarepta and Pfizer. No updates were provided on the current status of Genethon’s program (a fourth company developing a similar drug). No one would estimate the cost per patient for treatment.

Current Status of programmes

Solid Biosciences

Solid Biosciences are running a randomised, controlled, open label, single ascending dose trial.

Solid has a ‘delayed treatment’ arm and all patients know whether or not they are getting treatment . After passing screening, patients are randomized to either the treatment or delayed treatment arm. If on the delayed treatment arm, they will be followed for that one year then, assuming they continue meet eligibility criteria, will receive SGT-001.

They plan to recruit between 16-32 non-ambulatory adolescents and ambulatory children. The clinical trial has been initiated in Florida. It was a primary endpoint of safety and efficacy looking at microdystrophin expression. There will also be muscle function and strength tests, cardiac and respiratory function will be evaluated along with muscle mass area and composition (MRI). The trial is for 24 months with three biopsies. One at baseline before the drug is administered (if you are placed into the delayed treatment arm you will not have a biopsy until just before the drug is administered). There will be a second biopsy at one of the intermediate time points of 45 days, 3, 6 or 9 months and then the final third biopsy at 12 months.

They dosed the first adolescent patient in February 2018. The FDA then placed IGNITE DMD on clinical hold in March due to a Serious Adverse Reaction. The event fully resolved and the patient returned to his normal activities. The Principle Investigator Dr Barry Byrne & his team at the University of Florida provided exceptional patient care. In June 2018 the FDA lifted clinical hold and Solid are reinitiating clinical activities. Solid now plans to dose several children prior to dosing more adolescents.

Nationwide/ Sarepta

Dr Mendell is running an open label trial design at Nationwide children’s hospital in Ohio. The trial has 12 subjects with DMD enrolled in 2 cohorts.

Cohort A: 6 subjects; 3 months-3 years of age

Cohort B: 6 subjects; 4-7 years of age

Inclusion criteria;

Confirmed DMD mutation between 18-58, inclusive

AAVrh74 antibodies <1:50 titer

They presented results from the 4 patients they have dosed. They showed that data was consistent with preclinical results. There was widespread micro-dystrophin expression, upregulation of the DAPC complex. Significant reduction in the CK. Vector genome copy levels (>1 copy/nucleus) are consistent with robust micro-dystrophin protein expression. Use of the MHCK7 promoter will potentially after DMD disease natural history related cardiac expression.

They plan to initiate another trial in the US using the same age range of boys with a placebo arm. They believe the placebo arm is a necessity to bringing a quicker regulatory approval.  


Pfizer have a current phase 1b Safety Study. They are recruiting boys aged between 5-12 with DMD who are ambulant and on daily steroids and are negative to AAV9 Nab antibodies. They will be given a single intravenous infusion. There will be staggered dosing for both cohorts, 6 weeks between subjects 1-2 and 3 weeks between subjects 2-6. The primary endpoint will be safety through 12 months with other endpoints looking at Dystrophin expression and transduction and long-term safety through 5 years.


They currently have 3 sites activated in the US. They have screened 4 boys with 1 screening failure. Enrolled 3 boys and dosed 3 boys.

They have invested $100 million dollars to try and increase their manufacturing capabilities to allow them to be able to make a commercial supply.

How does gene therapy with CRISPR/Cas9 differ from AAV microdystrophin?

AAV-microdystrophin involves the use of a virus to deliver an extra copy of a miniaturised dystrophin. This does not integrate with the cell’s own DNA and stays in the nucleus. It won’t last for ever as it will eventually be diluted over time as the cell undergoes repeated rounds of replication.

CRISPR/Cas9 leads to permanent changes in the DNA.

Issues to consider in AAV Mediated delivery of CRISPR/Cas9;

Immune response to virus prevents re-administration of the same serotype.

Immune response to Cas9 will trigger myostatis (muscle inflammation)

AAV has been reported to integrate into the cut sites

Gene editing: CRISPR/Cas9: Must be adapted for each gene mutation. Can lead to more functional dystrophins - depending on the mutation. The best way to deliver remains uncertain. Gene editing with CRISP/Cas9 - lots of questions around the future potential. Gene editing could produce larger and more functional dystrophins.

It is extremely important to understand that gene editing is a long way away from entering clinical trials and it is important that families follow standards of care. Families commented they were holding off starting steroids because they were waiting for CRSPR trials to start. This was very worrying for the panel of experts. the current advice from the panel was very much that we such stay focused on the current AAV-related studies.

If you have any questions please email [email protected]  



Published on 2 July 2018

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