Duchenne foundation funds research leading to first-in-human clinical study

By Jenni Spinner

- Last updated on GMT


Related tags Duchenne muscular dystrophy preclinical Rare disease Precision medicine

The research taking place at Nationwide Children’s Hospital is seeking a treatment for a rare Duchenne muscular dystrophy mutation.

According to CureDuchenne, an organization dedicated to furthering research and care for Duchenne muscular dystrophy (DMD), Kevin Flanigan (director of the Center for Gene Therapy) has used gene therapy to treat two patients carrying the rare Duplication 2 mutation. The organization reportedly began Flanigan’s early work in the area 10 years ago, continuing through the development’s preclinical phase.

Outsourcing-Pharma (OSP) recently talked with CureDuchenne CEO and founder Debra Miller (DM) about the most recent Duplication 2 study, the organization’s mission to attain a cure for the rare and deadly disease, and her personal experience with DMD.a

OSP: Please tell us about CureDuchenne—who you are, what you do, and the programs and projects you’ve got going on.

DM: CureDuchenne is the largest Duchenne organization, including programs in research, patient care and support, biobank services and advocacy.  Our mission is our name; to cure Duchenne muscular dystrophy.

CureDuchenne has provided funding to 15 projects that have progressed to human clinical trials, two of them receiving FDA approval.  We use a venture philanthropy model with invests in biotech companies and re-deploy proceeds from successful investments, back into further research.

OSP: Could you please tell us about Duchenne, and about the Duplication 2 mutation?

DM: Duchenne is caused by a defect on the dystrophin gene, the largest gene in the body.  When one or more exons (pieces of DNA that must fit together to make the dystrophin protein) are deleted, duplicated or otherwise out of order, the protein making mechanism stops.

The majority of Duchenne cases can be grouped together in the “hotspot” region of the gene, and the first therapies being investigated and approved, address the most common mutations.  Early on, CureDuchenne took a serious interest in rare Duchenne mutations; just because a boy was unlucky enough to have a rare mutation in addition to having a rare disease, this should not exclude them from a therapy.

Over 10 years ago, CureDuchenne connected with Dr. Kevin Flanigan, who was also interested in rare mutations.  In 2010, CureDuchenne provided funding to Dr. Flanigan’s lab to create a custom mouse that carries a duplicate exon 2. 

Over the next 10 years, CureDuchenne provided two additional grants to Dr. Flanigan to test U7 exon skipping of duplication 2 in this mouse model and complete the preclinical work that would lead to a human clinical trial.

The Duplication 2 mutation was interesting because if you are able to completely skip (mask) one copy of exon 2, you would end up with “wild-type” (normal) dystrophin production.  If, instead, the targeting is less precise and you mask both copies of exon 2, the dystrophin protein was still produced, thanks to an internal ribosome entry site (IRES). 

The IRES basically kick starts the production of a functional dystrophin protein at exon 6.  This provided a safe target to employ a novel therapeutic approach.

OSP: Please tell us about the Center for Gene Therapy—has CureDuchenne worked with them in the past, or have they tackled Duchenne-related research previously?

DM: The Gene Therapy Center at Nationwide Children’s Hospital has a significant focus on neuromuscular diseases, including Duchenne.  In 2010, CureDuchenne funded a biotech company, Sarepta that worked closed with Nationwide for a first-generation exon skipping program later called Exondys 51, which became the first therapy approved for Duchenne; Sarepta then turned a great deal of focus on gene therapy and continues to work closely with Nationwide.

OSP: Please tell us about study, the gene-therapy vector and the two boys.

DM: Nationwide Children’s licensed the technology for U7 exon skipping for duplication 2, as well as a couple additional exons, to Audentes.  Audentes was subsequently acquired by Astellas, a large pharmaceutical company.  The development of these therapies is ongoing, albeit, possibly delayed by Covid. 

Dr. Flanigan reserved the right to treat two patients, who remain anonymous.  We are anxiously awaiting news of their progress and hopeful that many more Duchenne patients will be able to take advantage of Dr. Flanigan’s discovery.

OSP: What’s the next step?

DM: We believe that another biotech company has licensed this U7 technology for at least one other exon program, exon 44.  But, this has not been publicly disclosed. 

Since this is the exon skipping program that my son requires, I’m obviously anxious to see that it gets developed quickly and that it does not sit on a shelf due to competition with existing exon skipping programs.

OSP: Finally, what’s one thing you’d like people to know about Duchenne?

DM: Duchenne is a 100% fatal disease; most boys lose their ability to walk by the age of 15 and succumb to the disease by the time they are in their mid-twenties.  CureDuchenne’s funded research has now progressed to phase III trials and we have real hope.

We funded a gene therapy company that was acquired by Pfizer in 2016.  The patients in the first gene therapy trial seem to be doing very well.  Unfortunately, gene therapy trials only enroll very young patients. 

At this point, I believe it is safe to say, we will have a cure for Duchenne.  Our challenge now, is to make sure that everyone affected by this terrible disease has a cure.  I know we can do it!

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