Preclinical research of Nationwide exon 2 skipping for duplication 2

Exon 2 skipping therapy to induce Internal Ribosomal Entry Site (IRES) activation in Duchenne patients with exon 2 duplications

Questions and Answers

What stage is this research?

This research is pre-clinical, meaning it has not advanced to clinical trials involving people yet. The first-in-human trial is anticipated to begin in the third quarter of 2018.

What steps need to be completed before moving into a clinical trial?

Virus manufacturing for a first-in-human trial is complete. Pre-clinical, IND-enabling toxicity studies are essentially complete. IND submission is anticipated in summer 2018.

What is your best estimate for the length of time it will take to move this research into clinical trials?

4 months.

What is the goal or purpose of this study?

The goal of this study is to induce skipping of either one of both copies of exon 2 in patients with exon 2 duplications.

We intended to induce exon skipping by the use of a virus carrying several copies of a modified small nuclear RNA (U7snRNA) targeted to exon 2, where it interferes with splicing.

Skipping of one copy of exon 2 will be expected to result in a wild-type Duchenne transcript and expression of a full-length dystrophin protein. Skipping of both copies of exon 2 will be expected to result in the activation of an IRES in exon 5 that results in the production of a highly functional version of the dystrophin protein, which was discovered in patients with very mild Becker who were ambulant into their seventh decade.

Who is funding this study?

The preclinical development of this study has been funded by CureDuchenne and the Beauhawks Foundation. Manufacturing of the clinical viral vector lot has been funded by the Beauhawks Foundation. Discussions for funding for the clinical trial are underway.

Who will be eligible to participate in this study?

The final enrollment criteria are not set, but we anticipate enrolling pre-ambulant (> age 6 months) and ambulant patients who carry a duplication of exon 2.

What do I have to do if I decide to participate in this study?

This study will involve frequent visits to Nationwide Children’s Hospital. A pre-enrollment check for antibodies to the virus will be performed.

Delivery of the vector will likely require sedation and delivery to both legs via a catheter.

Muscle biopsies will be required at several time points: before and 12 weeks after vector delivery (open biopsies), and at 6 and 12 months after vector delivery (needle biopsies).

How long will this study last, and will I have access to the drug/treatment once the study has ended?

The study will require follow up for two years after injection.

Patients who participate in the trial are unlikely to be eligible for later gene delivery with the same vector, due to the expected development of antibodies to the viral capsid. However, animal studies suggest that genes delivered by AAV viruses will last for years.

If the treatment were to be approved by the FDA, treatments such as immunosuppression or plasmapheresis to clear anti-AAV antibodies may allow future treatment, although this cannot be guaranteed at present.

Why should I consider participating in this study?

Patients who naturally express the IRES-driven isoform of the dystrophin protein walk in to their seventh decade.

Studies in an animal model of exon 2 duplication Duchenne show that skipping can be done very efficiently with the virus.

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